* 600837

GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF


HGNC Approved Gene Symbol: GDNF

Cytogenetic location: 5p13.2     Genomic coordinates (GRCh38): 5:37,812,677-37,840,041 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5p13.2 {Hirschsprung disease, susceptibility to, 3} 613711 AD 3

TEXT

Cloning and Expression

Lin et al. (1993) isolated a specific dopaminergic neurotrophic protein, designated 'glial cell line-derived neurotrophic factor' (GDNF), from a rat B49 glial cell line. The corresponding cDNA was cloned from both human and rat cDNA libraries. The predicted 211-amino acid sequences of the 2 proteins showed 93% homology. The human GDNF precursor is processed to a mature 134-amino acid protein with 2 potential N-linked glycosylation sites; it exists as a homodimer. The mature protein contains 7 conserved cysteine residues spaced similarly to members of the TGF-beta superfamily (see 190180).


Mapping

Schindelhauer et al. (1995) mapped the GDNF gene to human chromosome 5p13.1-p12 by fluorescence in situ hybridization (FISH). By study of a cell hybrid panel and by FISH, Bermingham et al. (1995) mapped the GDNF gene to 5p13.3-p13.1.


Gene Function

Lin et al. (1993) found that recombinant human GDNF specifically promoted the survival and differentiation of dopaminergic neurons in rat embryonic midbrain cell cultures. GDNF also enhanced high-affinity uptake of dopamine in these cells. No effect of GDNF was seen on GABAergic or serotonergic neurons or astrocytes. Schaar et al. (1993) identified Gdnf transcripts in the substantia nigra and in type 1 astrocytes of rat basal forebrain. Recombinant GDNF promoted the survival and differentiation of dopaminergic neurons in embryonic midbrain cultures and promoted their uptake of dopamine.

Oppenheim et al. (1995) showed that recombinant human GDNF could rescue avian motor neurons from programmed cell death. In vivo, GDNF rescued avian and murine spinal motor neurons from death caused by axotomy. Beck et al. (1995) used GDNF to prevent loss of tyrosine hydroxylase (TH; 191290)-expressing neurons in the substantia nigra of adult rat brains after transfection of their axons within the medial forebrain bundle. Tomac et al. (1995) showed that GDNF injected over the substantia nigra or in the striatum of mice could protect cells from the effects of the neurotoxin MPTP in vivo, suggesting a possible use in the treatment of Parkinson disease (168600) since MPTP is known to damage dopamine neurons specifically.

Durbec et al. (1996) showed that GDNF is a ligand for the tyrosine kinase receptor RET (164761). Treanor et al. (1996) showed that GDNF acts through the GDNF receptor-1 (GFRA1; 601496).

In a Xenopus nerve-muscle coculture system, Wang et al. (2001) demonstrated that long-term treatment with GDNF resulted in increased presynaptic transmitter release via enhanced calcium influx through N-type calcium channels. These changes resulted in increased spontaneous and evoked synaptic currents at the neuromuscular junction. GDNF increased the expression of frequenin (603315) in cultured motoneurons, and anti-frequenin blockade attenuated the effects of GDNF, suggesting that frequenin acts downstream of GDNF. The findings showed that frequenin and GDNF mediate long-term synaptic plasticity.

Japon et al. (2002) found GDNF, GFRA1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Strong positive immunostaining was found for c-RET in all of the human GH (139250)-secreting pituitary adenomas screened as well as in 50% of human ACTH (176830)-producing pituitary adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. GFRA1 was detected in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. The authors concluded that expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.

Using gene expression profiling, Iwashita et al. (2003) determined that genes associated with Hirschsprung disease (HSCR; see 142623 and 613711) were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. Among the genes with highest expression were GDNF, SOX10 (602229), GFRA1, and EDNRB (131244). The highest expression was seen in RET, which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by Iwashita et al. (2003) were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis.

Therapeutic Use in Primates and Humans

In rodents, GDNF stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Gash et al. (1996) found that GDNF injected intracerebrally into rhesus monkeys that had had the symptomatology and pathophysiologic features of MPTP-induced Parkinson disease displayed significant improvements in 3 of the cardinal symptoms of parkinsonism: bradykinesia, rigidity, and postural instability.

Kordower et al. (2000) tested lentiviral vector delivery of GDNF, or lenti-GDNF, for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson disease. The authors injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with MPTP. Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. Kordower et al. (2000) concluded that GDNF delivery using a lentiviral vector system could prevent nigrostriatal degeneration and induce regeneration in primate models of PD.

Gill et al. (2003) delivered GDNF directly into the putamen of 5 Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the MRIs that disappeared after lowering the concentration of GDNF. After 1 year, there were no serious clinical side effects, a 39% improvement in the off-medication motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living subscore. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.


Molecular Genetics

Hirschsprung Disease, Susceptibility to, 3

In a patient (5503) with Hirschsprung disease (see 142623 and 613711) with a known RET mutation and malrotation of the gut, Angrist et al. (1996) identified a mutation in the GDNF gene (600837.0001). The data suggested that RET and GDNF mutations may act in concert to produce an enteric phenotype.

Salomon et al. (1996) analyzed GDNF mutations in 173 Hirschsprung disease patients and concluded that mutations in GDNF per se are neither necessary nor sufficient to cause HSCR, but may influence susceptibility to the disease especially in conjunction with other loci such as RET.

In 1 of 36 patients with HSCR, Ivanchuk et al. (1996) identified a mutation in the GDNF gene (600837.0003). The patient did not have a mutation in the RET gene and there was no family history of the disorder. Ivanchuk et al. (1996) concluded that GDNF mutations may be causative in some cases of HSCR.

Eketjall and Ibanez (2002) characterized the effect of 4 mutations in the rat Gdnf gene on the ability of rat protein to bind and activate its receptors. These mutations corresponded to the substitutions R93W (600837.0001), D150N (600837.0002), T154S (600837.0003), and I211M (600837.0004) in the GDNF gene that were identified in patients with HSCR. Although none of the 4 mutations appeared to affect the ability of Gdnf to activate Ret, D150N and I211M resulted in a significant reduction in the binding affinity of Gdnf for the binding subunit of the receptor complex, Gfra1. Eketjall and Ibanez (2002) hypothesized that although none of the GDNF mutations identified to that time in HSCR patients were sufficient to cause HSCR, some may contribute to pathogenesis of the disorder in conjunction with other genetic lesions.

Borghini et al. (2002) produced 5 GDNF mutant proteins in COS-7 cells and tested their effect on RET-expressing neuroblastoma cells. The degree of RET receptor activation observed was comparable to that induced by the wildtype GDNF protein. This observation was consistent with the lack of a clear genotype-phenotype correlation of GDNF mutations in Hirschsprung disease patients.

Associations Pending Confirmation

Bahuau et al. (2001) reported a family with neurofibromatosis type I (NF1; 162200), in which 2 children had congenital megacolon due to intestinal neuronal dysplasia type B (601223). The 2 children were found to be doubly heterozygous for a mutation in the NF1 gene (613113) inherited from their mother and a mutation in the GDNF gene inherited from their father. Bahuau et al. (2001) suggested that GDNF/NF1 may act as a modifier of neurofibromin function in keeping with interaction between the RET and RAS pathways.


Animal Model

Gdnf -/- mice display congenital intestinal aganglionosis and renal agenesis (Moore et al., 1996).

Sanchez et al. (1996) found that Gdnf-null mice displayed complete renal agenesis owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also lacked enteric neurons, which probably explained the observed pyloric stenosis and dilation of the duodenum. However, ablation of the Gdnf gene did not affect differentiation and survival of dopaminergic neurons, at least during embryonic development.

Pichel et al. (1996) generated mice that lacked Gdnf expression by targeted mutagenesis. The phenotype indicated that Gdnf was required for effective branching of the ureter during early kidney development and for innervation of the gastrointestinal tract. Similarities between Gdnf- and RET-null phenotypes, in terms of enteric invasion for example, provided genetic evidence for RET/GDNF receptor/ligand interactions.

Experimental application of growth factors can alter the density and distribution of axon branches; hence, growth factor release may be one means by which target cells regulate the number of synaptic connections they receive. Nguyen et al. (1998) generated several lines of transgenic mice that overexpressed Gdnf under a muscle-specific (myogenin; 159980) promoter. Overexpression of Gdnf by muscle greatly increased the number of motor axons innervating neuromuscular junctions in neonatal mice. The extent of hyperinnervation correlated with the amount of Gdnf expressed in 4 transgenic lines. Overexpression of Gdnf by glia and overexpression of NTF3 (162660) and NTF4 (162662) did not cause hyperinnervation. During the period of greatest hyperinnervation (birth to 3 weeks postnatal), the Myo-Gdnf mice exhibited a tremor. At neonatal ages, the shaking was sufficiently obvious that transgenic animals could be distinguished from their littermates without error. Normal rodent neonates have a tremor that is most obvious during the first few postnatal days and gradually subsides over the next week, which may be analogous to 'jitteriness' in human neonates. Disappearance of tremor corresponded to the loss of multiple innervation in each transgenic line, as it did in wildtype animals.

Transgenic Gdnf loss-of-function and overexpression mouse models showed that the dosage of Gdnf produced by Sertoli cells regulated cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis (Meng et al., 2000). Meng et al. (2000) showed that gene-targeted mice with 1 Gdnf-null allele had depleted stem cell reserves, whereas mice overexpressing Gdnf showed accumulation of undifferentiated spermatogonia. These spermatogonia were unable to respond properly to differentiation signals and underwent apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors were regularly formed in older Gdnf-overexpressing mice. Meng et al. (2000) concluded that GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.

Messer et al. (2000) found that infusion of Gdnf into the midbrain ventral tegmental area of mice blocked certain biochemical adaptations to chronic morphine and cocaine exposure and also decreased animal drug sensitivity. Similar changes were seen in mice already exposed to chronic morphine, suggesting that Gdnf could reverse drug-induced plasticity. Animals infused with an anti-Gdnf antibody and those with targeted deletion of 1 allele of the Gdnf gene showed increased sensitivity to drug-induced biochemical changes and behavior. Chronic drug exposure was correlated with reduced phosphorylation of Ret, indicating a decrease in functional Gdnf signaling. The findings established a functional interaction between Gdnf and drugs of abuse in the mesolimbic dopamine system.

In mice, Boucher et al. (2000) demonstrated that Gdnf both prevented and reversed sensory abnormalities that developed in neuropathic pain models without affecting pain-related behavior in normal animals. GDNF reduced ectopic discharges within sensory neurons after nerve injury. Boucher et al. (2000) hypothesized that this may arise as a consequence of reversal by GDNF of the injury-induced plasticity of several sodium channel subunits, and argued that their findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

The arrest of dorsal root axonal regeneration at the transitional zone between the peripheral and central nervous system has repeatedly been described. Ramer et al. (2000) demonstrated that this regenerative barrier was surmountable with trophic support to damaged sensory axons. In adult rats with injured dorsal roots, treatment with nerve growth factor (NGF; 162030), NTF3, or GDNF, but not brain-derived neurotrophic factor (BDNF; 113505), resulted in selective regrowth of damaged axons across the dorsal root entry zone and into the spinal cord. Dorsal horn neurons were found to be synaptically driven by peripheral nerve stimulation in rats treated with NGF, NTF3, and GDNF, demonstrating functional reconnection. In behavioral studies, rats treated with NGF and GDNF recovered sensitivity to noxious heat and pressure. Ramer et al. (2000) concluded that neurotrophic factor treatment may serve as a viable treatment in promoting recovery from root avulsion injuries.

Shen et al. (2002) found that heterozygous Gdnf +/- mutant mice recapitulated complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of 1 functioning Gdnf allele caused a spectrum of defects in gastrointestinal motility and predisposed the mutant mice to HSCR-like phenotypes. As many as 1 in 5 Gdnf +/- mutant mice died shortly after birth. Using a transgenic marking strategy, Shen et al. (2002) identified hypoganglionosis of the gastrointestinal tract as a developmental defect that rendered the mutant mice susceptible to clinical symptoms of HSCR.

Anitha et al. (2006) studied the effects of hyperglycemic exposure on primary enteric rat neurons and observed significantly increased apoptosis, with decreased Akt (see 164730) phosphorylation and enhanced nuclear translocation of Foxo3a (602681). Treatment of enteric neurons with GDNF ameliorated these changes. The pathophysiologic effects of hyperglycemia observed in diabetic mice, including apoptosis, reduced Akt phosphorylation, loss of inhibitory neurons, and motility changes, were reversed in transgenic mice overexpressing Gdnf. Anitha et al. (2006) concluded that hyperglycemia induces neuronal loss through a reduction in Akt-mediated survival signaling and that these effects are reversed by GDNF.

In a rat operant ethanol self-administration model, Carnicella et al. (2008) found that GDNF infusion resulted in rapid and dose-dependent reduction in ethanol, but not sucrose, self-administration. A GDNF-mediated decrease in ethanol consumption (see 103780) was also observed in rats with a history of high voluntary ethanol intake. The action of GDNF on ethanol consumption was specific to the ventral tegmental area (VTA), since infusion into the substantia nigra did not affect responses to ethanol. GDNF administration activated the MAPK (176948) signaling pathway in the VTA, and inhibition of the MAPK pathway in the VTA blocked reduction of ethanol self-administration by GDNF. Carnicella et al. (2008) suggested that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.

Retinal Degeneration

The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the retinal pigment epithelium (RPE) fails to phagocytose outer segments that have been shed, and photoreceptor cells subsequently die. Lawrence et al. (2004) found that engineered Schwann cells sustained retinal structure and function in the dystrophic RCS rat. Cells overexpressing Gdnf or Bdnf had a greater effect on photoreceptor survival than the parent line or sham surgery. The authors concluded that their study demonstrated that ex vivo gene therapy and subsequent cell transplantation could be effective in preserving photoreceptors from the cell death that normally accompanies retinal degeneration.


ALLELIC VARIANTS ( 4 Selected Examples):

.0001 HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ARG93TRP
  
RCV000009301...

In 1 of 106 unrelated patients with Hirschsprung disease (HSCR3; 613711), Angrist et al. (1996) identified a heterozygous 277C-T transition in exon 2 of the GDNF gene, resulting in an arg93-to-trp (R93W) substitution. The patient also carried a mutation in the RET gene (164761). The GDNF mutation was inherited from the patient's unaffected father. The patient had short-segment HSCR and malrotation of the gut.

In a large family segregating HSCR, Salomon et al. (1996) identified the R93W mutation in 2 affected individuals and in 1 individual with severe constipation; these 3 patients also carried RET mutations. However, 4 unaffected family members also had both the R93W and RET mutations, and 2 affected family members did not have the R93W mutation. The mutation was not identified in 180 control chromosomes. Salomon et al. (1996) concluded that while GDNF mutations are not sufficient to cause HSCR, they may modulate disease susceptibility or phenotype, especially when present with RET mutations.

Exclusion Studies

Amiel et al. (1998) identified the R93W mutation in a male patient with congenital central hypoventilation syndrome (209880) and growth hormone deficiency (see 139250), but Amiel et al. (2003) showed that this patient also carried the pathogenic polyalanine expansion in the PHOX2B gene (603851.0001).


.0002 HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ASP150ASN
  
RCV000009304...

In a patient with Hirschsprung disease (HSCR3; 613711) and trisomy 21 (190685), Salomon et al. (1996) identified a G-to-A transition in the GDNF gene, resulting in an asp150-to-asn (D150N) substitution at the border of the first conserved domain of GDNF and immediately next to one of the cysteine residues. The mutation was inherited from the healthy father. The mutation was not identified in 180 control chromosomes.

Hofstra et al. (1997) identified the D150N mutation in 1 of 100 patients with HSCR. The mutation was identified in 1 of 300 control chromosomes. Hofstra et al. (1997) commented that this and other mutations may have an effect only in the context of particular mutations or polymorphisms of other genes or even external factors.


.0003 HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, THR154SER
  
RCV000009305

In a patient with sporadic long-segment Hirschsprung disease (HSCR3; 613711), Ivanchuk et al. (1996) identified a 460A-T transversion in the GDNF gene, resulting in a thr154-to-ser (T154S) substitution. The patient did not have a mutation in the RET gene (164761) and there was no family history of the disorder. The mutation was not detected in 150 normal control chromosomes. Ivanchuk et al. (1996) concluded that GDNF mutations may be causative in some cases of HSCR.


.0004 HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ILE211MET
  
RCV000009306

In a case with the classic form of Hirschsprung disease (HSCR3; 613711), Martucciello et al. (2000) identified a 630C-G transversion in the GDNF gene, resulting in an ile211-to-met (I211M) substitution.


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  29. Pichel, J. G., Shen, L., Sheng, H. Z., Granholm, A.-C., Drago, J., Grinberg, A., Lee, E. J., Huang, S. P., Saarma, M., Hoffer, B. J., Sariola, H., Westphal, H. GDNF is required for kidney development and enteric innervation. Cold Spring Harbor Symp. Quant. Biol. 61: 445-457, 1996. [PubMed: 9246473, related citations]

  30. Ramer, M. S., Priestley, J. V., McMahon, S. B. Functional regeneration of sensory axons into the adult spinal cord. Nature 403: 312-316, 2000. [PubMed: 10659850, related citations] [Full Text]

  31. Salomon, R., Attie, T., Pelet, A., Bidaud, C., Eng, C., Amiel, J., Sarnacki, S., Goulet, O., Ricour, C., Nihoul-Fekete, C., Munnich, A., Lyonnet, S. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nature Genet. 14: 345-347, 1996. [PubMed: 8896569, related citations] [Full Text]

  32. Sanchez, M. P., Silos-Santiago, I., Frisen, J., He, B., Lira, S. A., Barbacid, M. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382: 70-73, 1996. [PubMed: 8657306, related citations] [Full Text]

  33. Schaar, D. G., Sieber, B.-A., Dreyfus, C. F., Black, I. B. Regional and cell-specific expression of GDNF in rat brain. Exp. Neurol. 124: 368-371, 1993. [PubMed: 8287932, related citations] [Full Text]

  34. Schindelhauer, D., Schuffenhauer, S., Gasser, T., Steinkasserer, A., Meitinger, T. The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1. Genomics 28: 605-607, 1995. [PubMed: 7490108, related citations] [Full Text]

  35. Shen, L., Pichel, J. G., Mayeli, T., Sariola, H., Lu, B., Westphal, H. Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice. Am. J. Hum. Genet. 70: 435-447, 2002. [PubMed: 11774071, images, related citations] [Full Text]

  36. Tomac, A., Lindqvist, E., Lin, L.-F. H., Ogren, S. O., Young, D., Hoffer, B. J., Olson, L. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373: 335-339, 1995. [PubMed: 7830766, related citations] [Full Text]

  37. Treanor, J. J. S., Goodman, L., de Sauvage, F., Stone, D. M., Poulsen, K. T., Beck, C. D., Gray, C., Armanini, M. P., Pollock, R. A., Hefti, F., Phillips, H. S., Goddard, A., Moore, M. W., Buj-Bello, A., Davies, A. M., Asai, N., Takahashi, M., Vandlen, R., Henderson, C. E., Rosenthal, A. Characterization of a multicomponent receptor for GDNF. Nature 382: 80-83, 1996. [PubMed: 8657309, related citations] [Full Text]

  38. Wang, C.-Y., Yang, F., He, X., Chow, A., Du, J., Russell, J. T., Lu, B. Ca(2+) binding protein frequenin mediates GDNF-induced potentiation of Ca(2+) channels and transmitter release. Neuron 32: 99-112, 2001. [PubMed: 11604142, related citations] [Full Text]

  39. Woodward, E. R., Eng, C., McMahon, R., Voutilainen, R., Affara, N. A., Ponder, B. A. J., Maher, E. R. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum. Molec. Genet. 6: 1051-1056, 1997. [PubMed: 9215674, related citations] [Full Text]


Cassandra L. Kniffin - updated : 6/30/2009
Marla J. F. O'Neill - updated : 7/10/2006
Cassandra L. Kniffin - updated : 1/6/2006
Cassandra L. Kniffin - reorganized : 8/29/2005
Cassandra L. Kniffin - updated : 8/19/2005
Jane Kelly - updated : 6/14/2004
Ada Hamosh - updated : 8/26/2003
Ada Hamosh - updated : 3/31/2003
Michael B. Petersen - updated : 10/31/2002
John A. Phillips, III - updated : 10/8/2002
George E. Tiller - updated : 9/23/2002
Michael J. Wright - updated : 7/31/2002
Victor A. McKusick - updated : 2/21/2002
Ada Hamosh - updated : 11/7/2000
Ada Hamosh - updated : 10/19/2000
Ada Hamosh - updated : 2/23/2000
Ada Hamosh - updated : 1/20/2000
Victor A. McKusick - updated : 3/11/1998
Victor A. McKusick - updated : 10/30/1997
Victor A. McKusick - updated : 9/3/1997
Moyra Smith - updated : 1/28/1997
Moyra Smith - updated : 11/20/1996
Orest Hurko - updated : 3/26/1996
Creation Date:
Alan F. Scott : 10/4/1995
carol : 08/13/2021
carol : 04/06/2017
carol : 01/25/2011
joanna : 7/27/2010
terry : 12/1/2009
carol : 11/23/2009
wwang : 7/24/2009
ckniffin : 6/30/2009
alopez : 12/5/2007
wwang : 7/10/2006
terry : 7/10/2006
wwang : 5/24/2006
ckniffin : 5/15/2006
carol : 1/12/2006
ckniffin : 1/6/2006
carol : 8/29/2005
carol : 8/29/2005
ckniffin : 8/19/2005
terry : 7/19/2004
alopez : 6/14/2004
alopez : 8/26/2003
alopez : 8/26/2003
terry : 8/26/2003
alopez : 5/16/2003
alopez : 4/2/2003
alopez : 4/1/2003
terry : 3/31/2003
alopez : 3/18/2003
alopez : 2/20/2003
cwells : 10/31/2002
alopez : 10/8/2002
cwells : 9/23/2002
cwells : 8/1/2002
terry : 7/31/2002
terry : 2/27/2002
carol : 2/27/2002
cwells : 2/26/2002
terry : 2/21/2002
mgross : 11/7/2000
alopez : 10/20/2000
terry : 10/19/2000
alopez : 2/24/2000
terry : 2/23/2000
alopez : 1/20/2000
dkim : 12/10/1998
carol : 7/15/1998
alopez : 5/5/1998
alopez : 3/12/1998
terry : 3/11/1998
terry : 11/4/1997
terry : 10/30/1997
terry : 9/8/1997
terry : 9/3/1997
alopez : 7/10/1997
jamie : 2/4/1997
terry : 1/28/1997
mark : 1/27/1997
mark : 11/20/1996
terry : 11/12/1996
terry : 11/1/1996
terry : 4/15/1996
mark : 4/7/1996
mark : 3/26/1996
terry : 3/21/1996
mark : 3/21/1996
terry : 1/16/1996
mark : 1/10/1996
mark : 1/4/1996
mark : 12/5/1995
mark : 10/4/1995

* 600837

GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF


HGNC Approved Gene Symbol: GDNF

Cytogenetic location: 5p13.2     Genomic coordinates (GRCh38): 5:37,812,677-37,840,041 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
5p13.2 {Hirschsprung disease, susceptibility to, 3} 613711 Autosomal dominant 3

TEXT

Cloning and Expression

Lin et al. (1993) isolated a specific dopaminergic neurotrophic protein, designated 'glial cell line-derived neurotrophic factor' (GDNF), from a rat B49 glial cell line. The corresponding cDNA was cloned from both human and rat cDNA libraries. The predicted 211-amino acid sequences of the 2 proteins showed 93% homology. The human GDNF precursor is processed to a mature 134-amino acid protein with 2 potential N-linked glycosylation sites; it exists as a homodimer. The mature protein contains 7 conserved cysteine residues spaced similarly to members of the TGF-beta superfamily (see 190180).


Mapping

Schindelhauer et al. (1995) mapped the GDNF gene to human chromosome 5p13.1-p12 by fluorescence in situ hybridization (FISH). By study of a cell hybrid panel and by FISH, Bermingham et al. (1995) mapped the GDNF gene to 5p13.3-p13.1.


Gene Function

Lin et al. (1993) found that recombinant human GDNF specifically promoted the survival and differentiation of dopaminergic neurons in rat embryonic midbrain cell cultures. GDNF also enhanced high-affinity uptake of dopamine in these cells. No effect of GDNF was seen on GABAergic or serotonergic neurons or astrocytes. Schaar et al. (1993) identified Gdnf transcripts in the substantia nigra and in type 1 astrocytes of rat basal forebrain. Recombinant GDNF promoted the survival and differentiation of dopaminergic neurons in embryonic midbrain cultures and promoted their uptake of dopamine.

Oppenheim et al. (1995) showed that recombinant human GDNF could rescue avian motor neurons from programmed cell death. In vivo, GDNF rescued avian and murine spinal motor neurons from death caused by axotomy. Beck et al. (1995) used GDNF to prevent loss of tyrosine hydroxylase (TH; 191290)-expressing neurons in the substantia nigra of adult rat brains after transfection of their axons within the medial forebrain bundle. Tomac et al. (1995) showed that GDNF injected over the substantia nigra or in the striatum of mice could protect cells from the effects of the neurotoxin MPTP in vivo, suggesting a possible use in the treatment of Parkinson disease (168600) since MPTP is known to damage dopamine neurons specifically.

Durbec et al. (1996) showed that GDNF is a ligand for the tyrosine kinase receptor RET (164761). Treanor et al. (1996) showed that GDNF acts through the GDNF receptor-1 (GFRA1; 601496).

In a Xenopus nerve-muscle coculture system, Wang et al. (2001) demonstrated that long-term treatment with GDNF resulted in increased presynaptic transmitter release via enhanced calcium influx through N-type calcium channels. These changes resulted in increased spontaneous and evoked synaptic currents at the neuromuscular junction. GDNF increased the expression of frequenin (603315) in cultured motoneurons, and anti-frequenin blockade attenuated the effects of GDNF, suggesting that frequenin acts downstream of GDNF. The findings showed that frequenin and GDNF mediate long-term synaptic plasticity.

Japon et al. (2002) found GDNF, GFRA1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Strong positive immunostaining was found for c-RET in all of the human GH (139250)-secreting pituitary adenomas screened as well as in 50% of human ACTH (176830)-producing pituitary adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. GFRA1 was detected in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. The authors concluded that expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.

Using gene expression profiling, Iwashita et al. (2003) determined that genes associated with Hirschsprung disease (HSCR; see 142623 and 613711) were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. Among the genes with highest expression were GDNF, SOX10 (602229), GFRA1, and EDNRB (131244). The highest expression was seen in RET, which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by Iwashita et al. (2003) were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis.

Therapeutic Use in Primates and Humans

In rodents, GDNF stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Gash et al. (1996) found that GDNF injected intracerebrally into rhesus monkeys that had had the symptomatology and pathophysiologic features of MPTP-induced Parkinson disease displayed significant improvements in 3 of the cardinal symptoms of parkinsonism: bradykinesia, rigidity, and postural instability.

Kordower et al. (2000) tested lentiviral vector delivery of GDNF, or lenti-GDNF, for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson disease. The authors injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with MPTP. Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. Kordower et al. (2000) concluded that GDNF delivery using a lentiviral vector system could prevent nigrostriatal degeneration and induce regeneration in primate models of PD.

Gill et al. (2003) delivered GDNF directly into the putamen of 5 Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the MRIs that disappeared after lowering the concentration of GDNF. After 1 year, there were no serious clinical side effects, a 39% improvement in the off-medication motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living subscore. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.


Molecular Genetics

Hirschsprung Disease, Susceptibility to, 3

In a patient (5503) with Hirschsprung disease (see 142623 and 613711) with a known RET mutation and malrotation of the gut, Angrist et al. (1996) identified a mutation in the GDNF gene (600837.0001). The data suggested that RET and GDNF mutations may act in concert to produce an enteric phenotype.

Salomon et al. (1996) analyzed GDNF mutations in 173 Hirschsprung disease patients and concluded that mutations in GDNF per se are neither necessary nor sufficient to cause HSCR, but may influence susceptibility to the disease especially in conjunction with other loci such as RET.

In 1 of 36 patients with HSCR, Ivanchuk et al. (1996) identified a mutation in the GDNF gene (600837.0003). The patient did not have a mutation in the RET gene and there was no family history of the disorder. Ivanchuk et al. (1996) concluded that GDNF mutations may be causative in some cases of HSCR.

Eketjall and Ibanez (2002) characterized the effect of 4 mutations in the rat Gdnf gene on the ability of rat protein to bind and activate its receptors. These mutations corresponded to the substitutions R93W (600837.0001), D150N (600837.0002), T154S (600837.0003), and I211M (600837.0004) in the GDNF gene that were identified in patients with HSCR. Although none of the 4 mutations appeared to affect the ability of Gdnf to activate Ret, D150N and I211M resulted in a significant reduction in the binding affinity of Gdnf for the binding subunit of the receptor complex, Gfra1. Eketjall and Ibanez (2002) hypothesized that although none of the GDNF mutations identified to that time in HSCR patients were sufficient to cause HSCR, some may contribute to pathogenesis of the disorder in conjunction with other genetic lesions.

Borghini et al. (2002) produced 5 GDNF mutant proteins in COS-7 cells and tested their effect on RET-expressing neuroblastoma cells. The degree of RET receptor activation observed was comparable to that induced by the wildtype GDNF protein. This observation was consistent with the lack of a clear genotype-phenotype correlation of GDNF mutations in Hirschsprung disease patients.

Associations Pending Confirmation

Bahuau et al. (2001) reported a family with neurofibromatosis type I (NF1; 162200), in which 2 children had congenital megacolon due to intestinal neuronal dysplasia type B (601223). The 2 children were found to be doubly heterozygous for a mutation in the NF1 gene (613113) inherited from their mother and a mutation in the GDNF gene inherited from their father. Bahuau et al. (2001) suggested that GDNF/NF1 may act as a modifier of neurofibromin function in keeping with interaction between the RET and RAS pathways.


Animal Model

Gdnf -/- mice display congenital intestinal aganglionosis and renal agenesis (Moore et al., 1996).

Sanchez et al. (1996) found that Gdnf-null mice displayed complete renal agenesis owing to lack of induction of the ureteric bud, an early step in kidney development. These mice also lacked enteric neurons, which probably explained the observed pyloric stenosis and dilation of the duodenum. However, ablation of the Gdnf gene did not affect differentiation and survival of dopaminergic neurons, at least during embryonic development.

Pichel et al. (1996) generated mice that lacked Gdnf expression by targeted mutagenesis. The phenotype indicated that Gdnf was required for effective branching of the ureter during early kidney development and for innervation of the gastrointestinal tract. Similarities between Gdnf- and RET-null phenotypes, in terms of enteric invasion for example, provided genetic evidence for RET/GDNF receptor/ligand interactions.

Experimental application of growth factors can alter the density and distribution of axon branches; hence, growth factor release may be one means by which target cells regulate the number of synaptic connections they receive. Nguyen et al. (1998) generated several lines of transgenic mice that overexpressed Gdnf under a muscle-specific (myogenin; 159980) promoter. Overexpression of Gdnf by muscle greatly increased the number of motor axons innervating neuromuscular junctions in neonatal mice. The extent of hyperinnervation correlated with the amount of Gdnf expressed in 4 transgenic lines. Overexpression of Gdnf by glia and overexpression of NTF3 (162660) and NTF4 (162662) did not cause hyperinnervation. During the period of greatest hyperinnervation (birth to 3 weeks postnatal), the Myo-Gdnf mice exhibited a tremor. At neonatal ages, the shaking was sufficiently obvious that transgenic animals could be distinguished from their littermates without error. Normal rodent neonates have a tremor that is most obvious during the first few postnatal days and gradually subsides over the next week, which may be analogous to 'jitteriness' in human neonates. Disappearance of tremor corresponded to the loss of multiple innervation in each transgenic line, as it did in wildtype animals.

Transgenic Gdnf loss-of-function and overexpression mouse models showed that the dosage of Gdnf produced by Sertoli cells regulated cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis (Meng et al., 2000). Meng et al. (2000) showed that gene-targeted mice with 1 Gdnf-null allele had depleted stem cell reserves, whereas mice overexpressing Gdnf showed accumulation of undifferentiated spermatogonia. These spermatogonia were unable to respond properly to differentiation signals and underwent apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors were regularly formed in older Gdnf-overexpressing mice. Meng et al. (2000) concluded that GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.

Messer et al. (2000) found that infusion of Gdnf into the midbrain ventral tegmental area of mice blocked certain biochemical adaptations to chronic morphine and cocaine exposure and also decreased animal drug sensitivity. Similar changes were seen in mice already exposed to chronic morphine, suggesting that Gdnf could reverse drug-induced plasticity. Animals infused with an anti-Gdnf antibody and those with targeted deletion of 1 allele of the Gdnf gene showed increased sensitivity to drug-induced biochemical changes and behavior. Chronic drug exposure was correlated with reduced phosphorylation of Ret, indicating a decrease in functional Gdnf signaling. The findings established a functional interaction between Gdnf and drugs of abuse in the mesolimbic dopamine system.

In mice, Boucher et al. (2000) demonstrated that Gdnf both prevented and reversed sensory abnormalities that developed in neuropathic pain models without affecting pain-related behavior in normal animals. GDNF reduced ectopic discharges within sensory neurons after nerve injury. Boucher et al. (2000) hypothesized that this may arise as a consequence of reversal by GDNF of the injury-induced plasticity of several sodium channel subunits, and argued that their findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

The arrest of dorsal root axonal regeneration at the transitional zone between the peripheral and central nervous system has repeatedly been described. Ramer et al. (2000) demonstrated that this regenerative barrier was surmountable with trophic support to damaged sensory axons. In adult rats with injured dorsal roots, treatment with nerve growth factor (NGF; 162030), NTF3, or GDNF, but not brain-derived neurotrophic factor (BDNF; 113505), resulted in selective regrowth of damaged axons across the dorsal root entry zone and into the spinal cord. Dorsal horn neurons were found to be synaptically driven by peripheral nerve stimulation in rats treated with NGF, NTF3, and GDNF, demonstrating functional reconnection. In behavioral studies, rats treated with NGF and GDNF recovered sensitivity to noxious heat and pressure. Ramer et al. (2000) concluded that neurotrophic factor treatment may serve as a viable treatment in promoting recovery from root avulsion injuries.

Shen et al. (2002) found that heterozygous Gdnf +/- mutant mice recapitulated complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of 1 functioning Gdnf allele caused a spectrum of defects in gastrointestinal motility and predisposed the mutant mice to HSCR-like phenotypes. As many as 1 in 5 Gdnf +/- mutant mice died shortly after birth. Using a transgenic marking strategy, Shen et al. (2002) identified hypoganglionosis of the gastrointestinal tract as a developmental defect that rendered the mutant mice susceptible to clinical symptoms of HSCR.

Anitha et al. (2006) studied the effects of hyperglycemic exposure on primary enteric rat neurons and observed significantly increased apoptosis, with decreased Akt (see 164730) phosphorylation and enhanced nuclear translocation of Foxo3a (602681). Treatment of enteric neurons with GDNF ameliorated these changes. The pathophysiologic effects of hyperglycemia observed in diabetic mice, including apoptosis, reduced Akt phosphorylation, loss of inhibitory neurons, and motility changes, were reversed in transgenic mice overexpressing Gdnf. Anitha et al. (2006) concluded that hyperglycemia induces neuronal loss through a reduction in Akt-mediated survival signaling and that these effects are reversed by GDNF.

In a rat operant ethanol self-administration model, Carnicella et al. (2008) found that GDNF infusion resulted in rapid and dose-dependent reduction in ethanol, but not sucrose, self-administration. A GDNF-mediated decrease in ethanol consumption (see 103780) was also observed in rats with a history of high voluntary ethanol intake. The action of GDNF on ethanol consumption was specific to the ventral tegmental area (VTA), since infusion into the substantia nigra did not affect responses to ethanol. GDNF administration activated the MAPK (176948) signaling pathway in the VTA, and inhibition of the MAPK pathway in the VTA blocked reduction of ethanol self-administration by GDNF. Carnicella et al. (2008) suggested that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.

Retinal Degeneration

The Royal College of Surgeons (RCS) rat is a widely studied, classic model of recessively inherited retinal degeneration in which the retinal pigment epithelium (RPE) fails to phagocytose outer segments that have been shed, and photoreceptor cells subsequently die. Lawrence et al. (2004) found that engineered Schwann cells sustained retinal structure and function in the dystrophic RCS rat. Cells overexpressing Gdnf or Bdnf had a greater effect on photoreceptor survival than the parent line or sham surgery. The authors concluded that their study demonstrated that ex vivo gene therapy and subsequent cell transplantation could be effective in preserving photoreceptors from the cell death that normally accompanies retinal degeneration.


ALLELIC VARIANTS 4 Selected Examples):

.0001   HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ARG93TRP
SNP: rs36119840, gnomAD: rs36119840, ClinVar: RCV000009301, RCV000150719, RCV002512938, RCV003934815

In 1 of 106 unrelated patients with Hirschsprung disease (HSCR3; 613711), Angrist et al. (1996) identified a heterozygous 277C-T transition in exon 2 of the GDNF gene, resulting in an arg93-to-trp (R93W) substitution. The patient also carried a mutation in the RET gene (164761). The GDNF mutation was inherited from the patient's unaffected father. The patient had short-segment HSCR and malrotation of the gut.

In a large family segregating HSCR, Salomon et al. (1996) identified the R93W mutation in 2 affected individuals and in 1 individual with severe constipation; these 3 patients also carried RET mutations. However, 4 unaffected family members also had both the R93W and RET mutations, and 2 affected family members did not have the R93W mutation. The mutation was not identified in 180 control chromosomes. Salomon et al. (1996) concluded that while GDNF mutations are not sufficient to cause HSCR, they may modulate disease susceptibility or phenotype, especially when present with RET mutations.

Exclusion Studies

Amiel et al. (1998) identified the R93W mutation in a male patient with congenital central hypoventilation syndrome (209880) and growth hormone deficiency (see 139250), but Amiel et al. (2003) showed that this patient also carried the pathogenic polyalanine expansion in the PHOX2B gene (603851.0001).


.0002   HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ASP150ASN
SNP: rs76466003, gnomAD: rs76466003, ClinVar: RCV000009304, RCV000252402, RCV002054428

In a patient with Hirschsprung disease (HSCR3; 613711) and trisomy 21 (190685), Salomon et al. (1996) identified a G-to-A transition in the GDNF gene, resulting in an asp150-to-asn (D150N) substitution at the border of the first conserved domain of GDNF and immediately next to one of the cysteine residues. The mutation was inherited from the healthy father. The mutation was not identified in 180 control chromosomes.

Hofstra et al. (1997) identified the D150N mutation in 1 of 100 patients with HSCR. The mutation was identified in 1 of 300 control chromosomes. Hofstra et al. (1997) commented that this and other mutations may have an effect only in the context of particular mutations or polymorphisms of other genes or even external factors.


.0003   HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, THR154SER
SNP: rs104893891, ClinVar: RCV000009305

In a patient with sporadic long-segment Hirschsprung disease (HSCR3; 613711), Ivanchuk et al. (1996) identified a 460A-T transversion in the GDNF gene, resulting in a thr154-to-ser (T154S) substitution. The patient did not have a mutation in the RET gene (164761) and there was no family history of the disorder. The mutation was not detected in 150 normal control chromosomes. Ivanchuk et al. (1996) concluded that GDNF mutations may be causative in some cases of HSCR.


.0004   HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 3

GDNF, ILE211MET
SNP: rs121918536, gnomAD: rs121918536, ClinVar: RCV000009306

In a case with the classic form of Hirschsprung disease (HSCR3; 613711), Martucciello et al. (2000) identified a 630C-G transversion in the GDNF gene, resulting in an ile211-to-met (I211M) substitution.


See Also:

Pichel et al. (1996); Woodward et al. (1997)

REFERENCES

  1. Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simmoneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genet. 33: 459-460, 2003. [PubMed: 12640453] [Full Text: https://doi.org/10.1038/ng1130]

  2. Amiel, J., Salomon, R., Attie, T., Pelet, A., Trang, H., Mokhtari, M., Gaultier, C., Munnich, A., Lyonnet, S. Mutations of the RET-GDNF signaling pathway in Ondine's curse. (Letter) Am. J. Hum. Genet. 62: 715-717, 1998. [PubMed: 9497256] [Full Text: https://doi.org/10.1086/301759]

  3. Angrist, M., Bolk, S., Halushka, M., Lapchak, P. A., Chakravarti, A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nature Genet. 14: 341-343, 1996. [PubMed: 8896568] [Full Text: https://doi.org/10.1038/ng1196-341]

  4. Anitha, M., Gondha, C., Sutliff, R., Parsadanian, A., Mwangi, S., Sitaraman, S. V., Srinivasan, S. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway. J. Clin. Invest. 116: 344-356, 2006. [PubMed: 16453021] [Full Text: https://doi.org/10.1172/JCI26295]

  5. Bahuau, M., Pelet, A., Vidaud, D., Lamireau, T., Le Bail, B., Munnich, A., Vidaud, M., Lyonnet, S., Lacombe, D. GDNF as a candidate modifier in a type 1 neurofibromatosis (NF1) enteric phenotype. (Letter) J. Med. Genet. 38: 638-643, 2001. [PubMed: 11565554] [Full Text: https://doi.org/10.1136/jmg.38.9.638]

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Contributors:
Cassandra L. Kniffin - updated : 6/30/2009
Marla J. F. O'Neill - updated : 7/10/2006
Cassandra L. Kniffin - updated : 1/6/2006
Cassandra L. Kniffin - reorganized : 8/29/2005
Cassandra L. Kniffin - updated : 8/19/2005
Jane Kelly - updated : 6/14/2004
Ada Hamosh - updated : 8/26/2003
Ada Hamosh - updated : 3/31/2003
Michael B. Petersen - updated : 10/31/2002
John A. Phillips, III - updated : 10/8/2002
George E. Tiller - updated : 9/23/2002
Michael J. Wright - updated : 7/31/2002
Victor A. McKusick - updated : 2/21/2002
Ada Hamosh - updated : 11/7/2000
Ada Hamosh - updated : 10/19/2000
Ada Hamosh - updated : 2/23/2000
Ada Hamosh - updated : 1/20/2000
Victor A. McKusick - updated : 3/11/1998
Victor A. McKusick - updated : 10/30/1997
Victor A. McKusick - updated : 9/3/1997
Moyra Smith - updated : 1/28/1997
Moyra Smith - updated : 11/20/1996
Orest Hurko - updated : 3/26/1996

Creation Date:
Alan F. Scott : 10/4/1995

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