* 607928

WHIRLIN; WHRN


Alternative titles; symbols

CASK-INTERACTING PROTEIN, 98-KD; CIP98
KIAA1526


HGNC Approved Gene Symbol: WHRN

Cytogenetic location: 9q32     Genomic coordinates (GRCh38): 9:114,402,080-114,505,473 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q32 Deafness, autosomal recessive 31 607084 AR 3
Usher syndrome, type 2D 611383 AR 3

TEXT

Description

In rat brain, Whrn, or Cip98, interacts with a calmodulin-dependent serine kinase, Cask (300172), and may be involved in the formation of scaffolding protein complexes that facilitate synaptic transmission in the central nervous system (Yap et al., 2003).


Cloning and Expression

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned CIP98, which they designated KIAA1526. The deduced protein contains 963 amino acids. RT-PCR ELISA detected restricted expression of CIP98. Moderate levels were detected in adult and fetal whole brain, followed by adult pancreas, spleen, testis, and ovary. Low expression was detected in adult lung and liver and in fetal liver, and little to no expression was detected in heart, skeletal muscle, and kidney. Examination of specific brain regions revealed strong expression in amygdala, corpus callosum, and substantia nigra, and moderate expression in all other specific brain regions examined.

Yap et al. (2003) cloned rat Cip98. The deduced 920-amino acid protein contains 3 PDZ domains and a proline-rich region that separates PDZ2 from PDZ3, which is located at the C terminus. In situ hybridization and immunohistochemical staining demonstrated that Cip98 was expressed in certain neurons, including pyramidal cells in layers III to V of the cerebral cortex, projecting neurons in the thalamus, and interneurons in the cerebellum. Cip98 localized to both dendrites and axons. Cip98 showed an apparent molecular mass of 98 kD by Western blot analysis of rat brain lysates.

Mburu et al. (2003) demonstrated that the human WHRN gene is alternatively spliced to form a long and a short transcript. Northern blot analysis identified 2 transcripts of approximately 1.8 kb and 4 kb in liver and testis and a single 4-kb transcript in kidney, brain, heart, and lung. A strong Kozak sequence in both mouse and human exon 6 identified the putative ATG start of the short C-terminal transcript and predicted a protein of 465 amino acids with a molecular mass of 49.3 kD. In exon 1, the translation initiation site was identified by a Kozak consensus sequence preceded by an in-frame stop codon located 153 kb upstream. The deduced protein of 906 amino acids (441 amino acids longer than the short C-terminal isoform) has a molecular mass of 97.3 kD. The sequence of the encoded protein showed that the short C-terminal isoform contains 1 PDZ domain and 1 proline-rich domain, whereas the long isoform is composed of 3 PDZ domains and 1 proline-rich domain. The proline-rich domain located between the PDZ2 and PDZ3 domains contains several short stretches of polyproline. Mburu et al. (2003) found that the amino acid sequences of mouse and human WHRN are 88% identical across the entire coding sequence but 94.4% in the PDZ domains. The most closely homologous human protein was found to be harmonin (605242), with which whirlin shared 65% similarity in their 3 PDZ domains.

Belyantseva et al. (2005) identified 10 splice variants of mouse Whrn that were predicted to encode proteins ranging from 156 to 918 amino acids.


Gene Structure

Mburu et al. (2003) demonstrated that the human WHRN gene contains 12 exons. The short C-terminal isoform is encoded by 8 exons.


Mapping

By radiation hybrid analysis, Nagase et al. (2000) mapped the WHRN gene to chromosome 9.


Gene Function

Yap et al. (2003) determined that rat Cip98 interacted with Cask, a member of the membrane-associated guanylate kinase (MAGUK) family that organizes proteins at synapses. Cip98 colocalized with Cask along the dendritic processes of neurons.

By immunolocalization, Kikkawa et al. (2005) showed that whirlin localized to the tips of mouse stereocilia. Expression of whirlin was dynamic during stereocilia growth, demonstrating an ordered appearance and fade-out across the stereocilia rows and revealing a molecular gradation process starting with the taller stereocilia and traversing to the shorter stereocilia. Fade-out of whirlin in inner hair cells preceded that of outer hair cells, consistent with the earlier maturation of inner hair cell stereocilia. In myosin XVa (MYO15A; 602666) mutants in which stereocilia were shortened, whirlin expression in stereocilia tips was stalled and fade-out was accelerated. In whirlin mutants, myosin XVa was still expressed in stereocilia, but its appearance at the stereocilia tip was delayed. Kikkawa et al. (2005) concluded that whirlin expression is a critical and dynamic organizer for stereocilia elongation and actin polymerization.

Belyantseva et al. (2005) determined that the C-terminal PDZ ligand of mouse Myo15a interacted with the third PDZ domain of whirlin, and this interaction was required for the targeting of whirlin to the tips of stereocilia. Reintroduction of Myo15a into hair cells of Myo15a-deficient mice restored the recruitment of endogenous whirlin to the tips of stereocilia. Belyantseva et al. (2005) concluded that the interaction of MYO15A with whirlin is a key event in hair bundle morphogenesis.

Delprat et al. (2005) showed that the myosin XVa SH3-MyTH4 region bound to the short isoform of whirlin, whereas the C-terminal MyTH4-FERM region of myosin XVa bound to the PDZ1 and PDZ2 domains of the long whirlin isoform. The transmembrane netrin-G1 ligand (NGL1; 608817) bound to the PDZ1 and PDZ2 domains of whirlin. Delprat et al. (2005) hypothesized that interaction between whirlin and NGL1 may be involved in the stabilization of interstereociliar links.

By yeast 2-hybrid analysis of a mouse embryo cDNA library, Mburu et al. (2006) found that whirlin interacted with p55 (MPP1; 305360), a member of the MAGUK family. p55 was expressed in mouse outer hair cells in long stereocilia that made up the stereocilia bundle and in surrounding shorter stereocilia structures. Since p55 and protein 4.1R (EPB41; 130500) form complexes critical for actin cytoskeletal assembly in erythrocytes, Mburu et al. (2006) proposed that p55 and whirlin may have a similar role in hair cell stereocilia.

Using immunohistochemical analysis, van Wijk et al. (2006) showed that whirlin colocalized with Ush2a isoform B (608400) and Vlgr1b (602851) in synaptic regions of photoreceptor cells in adult rat retina and outer hair cells of adult rat cochlea. Van Wijk et al. (2006) hypothesized that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of photoreceptor and hair cell synapses.

Using yeast 2-hybrid analysis, Maerker et al. (2008) found that the C terminus of human SANS (USH1G; 607696) interacted with the N-terminal region of whirlin in a bovine retina cDNA library. In mouse retina, both proteins colocalized at synapses in the outer plexiform layer and in the outer limiting membrane, the inner segment, and the ciliary region of photoreceptor cells. Within the ciliary region, high resolution analysis revealed that Sans and whirlin colocalized in the connecting cilium and basal body complex. Maerker et al. (2008) showed that Sans provided a link to the microtubule transport machinery, whereas whirlin appeared to anchor 2 retinal transmembrane proteins, Ush2a isoform b and Vlgr1b, to specific membrane domains. Maerker et al. (2008) concluded that this network of proteins may cooperate to regulate cargo transfer from inner segment transport carriers to the ciliary transport system of photoreceptors.


Molecular Genetics

Autosomal Recessive Deafness 31

In affected members of a consanguineous multiplex Palestinian family with autosomal recessive nonsyndromic deafness mapping to chromosome 9q32-q34 (DFNB31; 607084), originally reported by Mustapha et al. (2002), Mburu et al. (2003) identified a homozygous nonsense mutation in the WHRN gene (607928.0001).

In affected members of a consanguineous Tunisian family with autosomal recessive nonsyndromic deafness, Tlili et al. (2005) identified a homozygous frameshift mutation in the WHRN gene (607928.0006) that segregated with the phenotype in the family.

Usher Syndrome Type IID

In 2 German sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383), Ebermann et al. (2007) identified compound heterozygosity for a nonsense (607928.0002) and a splice site mutation (607928.0003) in the WHRN gene. The authors noted that whereas mutations affecting the C-terminal half of whirlin have been reported in patients with nonsyndromic deafness (DFNB31), the alterations identified in this USH2 family both affect the long isoform of whirlin, suggesting that it is crucial for retinal function.

In 2 of 31 French USH2 patients who were not linked to the USH2A locus (608400), Besnard et al. (2012) identified homozygosity and compound heterozygosity for WHRN mutations, respectively (607928.0004; 607928.0005). Besnard et al. (2012) concluded that WHRN mutations account for a very small proportion of mutations causing USH2 (1.3%).


Animal Model

The 'whirler' mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicated that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair and outer hair cells. By BAC-mediated transgene correction of the mouse phenotype and mutation analysis, Mburu et al. (2003) identified the causative gene as encoding a PDZ protein they designated whirlin. They found that the same gene is mutant in the human autosomal recessive deafness locus DFNB31.


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 DEAFNESS, AUTOSOMAL RECESSIVE 31

DFNB31, ARG778TER
  
RCV000002808...

In affected members of a consanguineous Palestinian family with autosomal recessive nonsyndromic deafness mapping to chromosome 9q32-q34 (DFNB31; 607084), originally described by Mustapha et al. (2002), Mburu et al. (2003) identified a 2332C-T transition in exon 10 of the WHRN gene, resulting in an arg778-to-ter (R778X) substitution and a truncated protein of 777 amino acids lacking the third PDZ domain. The mutation was present in homozygous state in 6 affected members of the family and was either absent or present in heterozygous state in unaffected members of the family. The mutation was not found in 100 unrelated Jordanian individuals with normal hearing or in 150 probands from multiplex families with autosomal recessive forms of nonsyndromic deafness, indicating that this is a rare form of deafness.


.0002 USHER SYNDROME, TYPE IID

DFNB31, GLN103TER
  
RCV000002809

In 2 German sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383), Ebermann et al. (2007) identified compound heterozygosity for a 307C-T transition in exon 1 of the WHRN gene, resulting in a gln103-to-ter (Q103X) substitution, and a splice site mutation (837+1G-A; 607928.0003) in the donor site of intron 2, causing in-frame skipping of exon 2. The splice site mutation was predicted to result in an aberrant long isoform of whirlin lacking 73 residues (9 from PDZ1, the 53-residue linker region, and 11 from PDZ2). The mutations were not found in 100 healthy controls.


.0003 USHER SYNDROME, TYPE IID

DFNB31, IVS2DS, G-A, +1
  
RCV000002810

For discussion of the splice site mutation in the WHRN gene (837+1G-A) that was found in compound heterozygous state in 2 sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383) by Ebermann et al. (2007), see 607928.0002.


.0004 USHER SYNDROME, TYPE IID

DFNB31, 1-BP DEL, 737C
  
RCV000024377...

In a patient with type II Usher syndrome (USH2D; 611383), Besnard et al. (2012) identified homozygosity for a 1-bp deletion (737delC) in exon 2 of the WHRN gene, causing a frameshift (Pro246fs) predicted to result in a premature termination codon. In an unrelated USH2 patient, Besnard et al. (2012) identified compound heterozygosity for 737delC and a 1-bp duplication (680dupG; 607928.0005) in exon 2 of the WHRN gene, also causing a frameshift (Tyr228fs) predicted to result in premature termination.


.0005 USHER SYNDROME, TYPE IID

DFNB31, 1-BP DUP, 680G
  
RCV000024378...

For discussion of the 1-bp duplication (680dupG) in the WHRN gene that was found in compound heterozygous state in a patient with type II Usher syndrome (USH2D; 611383) by Besnard et al. (2012), see 607928.0004.


.0006 DEAFNESS, AUTOSOMAL RECESSIVE 31

DFNB31, 1-BP DEL, 2423G
  
RCV000190401

By mutation screening of the WHRN gene in affected members of a Tunisian family with autosomal recessive nonsyndromic deafness showing linkage to the DFNB31 (607084) region, Tlili et al. (2005) identified homozygosity for a 1-bp deletion (c.2423delG, NM_015404.1), producing a frameshift and resulting in a premature stop codon (Gly808AspfsTer11 in the long isoform; Gly457AspfsTer11 in the short isoform). The deletion was found in heterozygous state in the unaffected parents and an unaffected sib.


REFERENCES

  1. Belyantseva, I. A., Boger, E. T., Naz, S., Frolenkov, G. I., Sellers, J. R., Ahmed, Z. M., Griffith, A. J., Friedman, T. B. Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nature Cell Biol. 7: 148-156, 2005. [PubMed: 15654330, related citations] [Full Text]

  2. Besnard, T., Vache, C., Baux, D., Larrieu, L., Abadie, C., Blanchet, C., Odent, S., Blanchet, P., Calvas, P., Hamel, C., Dollfus, H., Lina-Granade, G., Lespinasse, J., David, A., Isidor, B., Morin, G., Malcolm, S., Tuffery-Giraud, S., Claustres, M., Roux, A.-F. Non-USH2A mutations in USH2 patients. Hum. Mutat. 33: 504-510, 2012. [PubMed: 22147658, related citations] [Full Text]

  3. Delprat, B., Michel, V., Goodyear, R., Yamasaki, Y., Michalski, N., El-Amraoui, A., Perfettini, I., Legrain, P., Richardson, G., Hardelin, J.-P., Petit, C. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly. Hum. Molec. Genet. 14: 401-410, 2005. [PubMed: 15590698, related citations] [Full Text]

  4. Ebermann, I., Scholl, H. P. N., Issa, P. C., Becirovic, E., Lamprecht, J., Jurklies, B., Millan, J. M., Aller, E., Mitter, D., Bolz, H. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum. Genet. 121: 203-211, 2007. [PubMed: 17171570, related citations] [Full Text]

  5. Kikkawa, Y., Mburu, P., Morse, S., Kominami, R., Townsend, S., Brown, S. D. M. Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium. Hum. Molec. Genet. 14: 391-400, 2005. [PubMed: 15590699, related citations] [Full Text]

  6. Maerker, T., van Wijk, E., Overlack, N., Kersten, F. F. J., McGee, J., Goldmann, T., Sehn, E., Roepman, R., Walsh, E. J., Kremer, H., Wolfrum, U. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum. Molec. Genet. 17: 71-86, 2008. [PubMed: 17906286, related citations] [Full Text]

  7. Mburu, P., Kikkawa, Y., Townsend, S., Romero, R., Yonekawa, H., Brown, S. D. M. Whirlin complexes with p55 at the stereocilia tip during hair cell development. Proc. Nat. Acad. Sci. 103: 10973-10978, 2006. [PubMed: 16829577, images, related citations] [Full Text]

  8. Mburu, P., Mustapha, M., Varela, A., Weil, D., El-Amraoui, A., Holme, R. H., Rump, A., Hardisty, R. E., Blanchard, S., Coimbra, R. S., Perfettini, I., Parkinson, N., and 12 others. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nature Genet. 34: 421-428, 2003. [PubMed: 12833159, related citations] [Full Text]

  9. Mustapha, M., Chouery, E., Chardenoux, S., Naboulsi, M., Paronnaud, J., Lemainque, A., Megarbane, A., Loiselet, J., Weil, D., Lathrop, M., Petit, C. DFNB31, a recessive form of sensorineural hearing loss, maps to chromosome 9q32-34. Europ. J. Hum. Genet. 10: 210-212, 2002. [PubMed: 11973626, related citations] [Full Text]

  10. Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331, related citations] [Full Text]

  11. Tlili, A., Charfedine, I., Lahmar, I., Benzina, Z., Mohamed, B. A., Weil, D., Idriss, N., Drira, M., Masmoudi, S., Ayadi, H. Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary non-syndromic recessive hearing loss. (Abstract) Hum. Mutat. 25: 503 only, 2005. Note: Full article online. [PubMed: 15841483, related citations] [Full Text]

  12. van Wijk, E., van der Zwaag, B., Peters, T., Zimmermann, U., te Brinke, H., Kersten, F. F. J., Marker, T., Aller, E., Hoefsloot, L. H., Cremers, C. W. R. J., Cremers, F. P. M., Wolfrum, U., Knipper, M., Roepman, R., Kremer, H. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum. Molec. Genet. 15: 751-765, 2006. [PubMed: 16434480, related citations] [Full Text]

  13. Yap, C. C., Liang, F., Yamazaki, Y., Muto, Y., Kishida, H., Hayashida, T., Hashikawa, T., Yano, R. CIP98, a novel PDZ domain protein, is expressed in the central nervous system and interacts with calmodulin-dependent serine kinase. J. Neurochem. 85: 123-134, 2003. [PubMed: 12641734, related citations] [Full Text]


Carol A. Bocchini - updated : 08/14/2015
Marla J. F. O'Neill - updated : 6/8/2012
Patricia A. Hartz - updated : 11/11/2009
Patricia A. Hartz - updated : 9/21/2009
George E. Tiller - updated : 12/11/2007
Marla J. F. O'Neill - updated : 8/21/2007
Patricia A. Hartz - updated : 10/3/2006
Patricia A. Hartz - updated : 5/20/2005
Victor A. McKusick - updated : 7/2/2003
Creation Date:
Patricia A. Hartz : 6/27/2003
carol : 10/11/2016
carol : 08/14/2015
carol : 8/13/2015
mcolton : 8/12/2015
terry : 6/8/2012
terry : 4/12/2012
alopez : 9/16/2011
terry : 9/9/2010
mgross : 11/16/2009
terry : 11/11/2009
mgross : 10/2/2009
terry : 9/21/2009
wwang : 12/28/2007
terry : 12/11/2007
wwang : 8/27/2007
terry : 8/21/2007
mgross : 10/5/2006
mgross : 10/5/2006
terry : 10/3/2006
wwang : 5/20/2005
alopez : 9/2/2003
alopez : 7/2/2003
terry : 7/2/2003
mgross : 6/30/2003

* 607928

WHIRLIN; WHRN


Alternative titles; symbols

CASK-INTERACTING PROTEIN, 98-KD; CIP98
KIAA1526


HGNC Approved Gene Symbol: WHRN

Cytogenetic location: 9q32     Genomic coordinates (GRCh38): 9:114,402,080-114,505,473 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q32 Deafness, autosomal recessive 31 607084 Autosomal recessive 3
Usher syndrome, type 2D 611383 Autosomal recessive 3

TEXT

Description

In rat brain, Whrn, or Cip98, interacts with a calmodulin-dependent serine kinase, Cask (300172), and may be involved in the formation of scaffolding protein complexes that facilitate synaptic transmission in the central nervous system (Yap et al., 2003).


Cloning and Expression

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned CIP98, which they designated KIAA1526. The deduced protein contains 963 amino acids. RT-PCR ELISA detected restricted expression of CIP98. Moderate levels were detected in adult and fetal whole brain, followed by adult pancreas, spleen, testis, and ovary. Low expression was detected in adult lung and liver and in fetal liver, and little to no expression was detected in heart, skeletal muscle, and kidney. Examination of specific brain regions revealed strong expression in amygdala, corpus callosum, and substantia nigra, and moderate expression in all other specific brain regions examined.

Yap et al. (2003) cloned rat Cip98. The deduced 920-amino acid protein contains 3 PDZ domains and a proline-rich region that separates PDZ2 from PDZ3, which is located at the C terminus. In situ hybridization and immunohistochemical staining demonstrated that Cip98 was expressed in certain neurons, including pyramidal cells in layers III to V of the cerebral cortex, projecting neurons in the thalamus, and interneurons in the cerebellum. Cip98 localized to both dendrites and axons. Cip98 showed an apparent molecular mass of 98 kD by Western blot analysis of rat brain lysates.

Mburu et al. (2003) demonstrated that the human WHRN gene is alternatively spliced to form a long and a short transcript. Northern blot analysis identified 2 transcripts of approximately 1.8 kb and 4 kb in liver and testis and a single 4-kb transcript in kidney, brain, heart, and lung. A strong Kozak sequence in both mouse and human exon 6 identified the putative ATG start of the short C-terminal transcript and predicted a protein of 465 amino acids with a molecular mass of 49.3 kD. In exon 1, the translation initiation site was identified by a Kozak consensus sequence preceded by an in-frame stop codon located 153 kb upstream. The deduced protein of 906 amino acids (441 amino acids longer than the short C-terminal isoform) has a molecular mass of 97.3 kD. The sequence of the encoded protein showed that the short C-terminal isoform contains 1 PDZ domain and 1 proline-rich domain, whereas the long isoform is composed of 3 PDZ domains and 1 proline-rich domain. The proline-rich domain located between the PDZ2 and PDZ3 domains contains several short stretches of polyproline. Mburu et al. (2003) found that the amino acid sequences of mouse and human WHRN are 88% identical across the entire coding sequence but 94.4% in the PDZ domains. The most closely homologous human protein was found to be harmonin (605242), with which whirlin shared 65% similarity in their 3 PDZ domains.

Belyantseva et al. (2005) identified 10 splice variants of mouse Whrn that were predicted to encode proteins ranging from 156 to 918 amino acids.


Gene Structure

Mburu et al. (2003) demonstrated that the human WHRN gene contains 12 exons. The short C-terminal isoform is encoded by 8 exons.


Mapping

By radiation hybrid analysis, Nagase et al. (2000) mapped the WHRN gene to chromosome 9.


Gene Function

Yap et al. (2003) determined that rat Cip98 interacted with Cask, a member of the membrane-associated guanylate kinase (MAGUK) family that organizes proteins at synapses. Cip98 colocalized with Cask along the dendritic processes of neurons.

By immunolocalization, Kikkawa et al. (2005) showed that whirlin localized to the tips of mouse stereocilia. Expression of whirlin was dynamic during stereocilia growth, demonstrating an ordered appearance and fade-out across the stereocilia rows and revealing a molecular gradation process starting with the taller stereocilia and traversing to the shorter stereocilia. Fade-out of whirlin in inner hair cells preceded that of outer hair cells, consistent with the earlier maturation of inner hair cell stereocilia. In myosin XVa (MYO15A; 602666) mutants in which stereocilia were shortened, whirlin expression in stereocilia tips was stalled and fade-out was accelerated. In whirlin mutants, myosin XVa was still expressed in stereocilia, but its appearance at the stereocilia tip was delayed. Kikkawa et al. (2005) concluded that whirlin expression is a critical and dynamic organizer for stereocilia elongation and actin polymerization.

Belyantseva et al. (2005) determined that the C-terminal PDZ ligand of mouse Myo15a interacted with the third PDZ domain of whirlin, and this interaction was required for the targeting of whirlin to the tips of stereocilia. Reintroduction of Myo15a into hair cells of Myo15a-deficient mice restored the recruitment of endogenous whirlin to the tips of stereocilia. Belyantseva et al. (2005) concluded that the interaction of MYO15A with whirlin is a key event in hair bundle morphogenesis.

Delprat et al. (2005) showed that the myosin XVa SH3-MyTH4 region bound to the short isoform of whirlin, whereas the C-terminal MyTH4-FERM region of myosin XVa bound to the PDZ1 and PDZ2 domains of the long whirlin isoform. The transmembrane netrin-G1 ligand (NGL1; 608817) bound to the PDZ1 and PDZ2 domains of whirlin. Delprat et al. (2005) hypothesized that interaction between whirlin and NGL1 may be involved in the stabilization of interstereociliar links.

By yeast 2-hybrid analysis of a mouse embryo cDNA library, Mburu et al. (2006) found that whirlin interacted with p55 (MPP1; 305360), a member of the MAGUK family. p55 was expressed in mouse outer hair cells in long stereocilia that made up the stereocilia bundle and in surrounding shorter stereocilia structures. Since p55 and protein 4.1R (EPB41; 130500) form complexes critical for actin cytoskeletal assembly in erythrocytes, Mburu et al. (2006) proposed that p55 and whirlin may have a similar role in hair cell stereocilia.

Using immunohistochemical analysis, van Wijk et al. (2006) showed that whirlin colocalized with Ush2a isoform B (608400) and Vlgr1b (602851) in synaptic regions of photoreceptor cells in adult rat retina and outer hair cells of adult rat cochlea. Van Wijk et al. (2006) hypothesized that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of photoreceptor and hair cell synapses.

Using yeast 2-hybrid analysis, Maerker et al. (2008) found that the C terminus of human SANS (USH1G; 607696) interacted with the N-terminal region of whirlin in a bovine retina cDNA library. In mouse retina, both proteins colocalized at synapses in the outer plexiform layer and in the outer limiting membrane, the inner segment, and the ciliary region of photoreceptor cells. Within the ciliary region, high resolution analysis revealed that Sans and whirlin colocalized in the connecting cilium and basal body complex. Maerker et al. (2008) showed that Sans provided a link to the microtubule transport machinery, whereas whirlin appeared to anchor 2 retinal transmembrane proteins, Ush2a isoform b and Vlgr1b, to specific membrane domains. Maerker et al. (2008) concluded that this network of proteins may cooperate to regulate cargo transfer from inner segment transport carriers to the ciliary transport system of photoreceptors.


Molecular Genetics

Autosomal Recessive Deafness 31

In affected members of a consanguineous multiplex Palestinian family with autosomal recessive nonsyndromic deafness mapping to chromosome 9q32-q34 (DFNB31; 607084), originally reported by Mustapha et al. (2002), Mburu et al. (2003) identified a homozygous nonsense mutation in the WHRN gene (607928.0001).

In affected members of a consanguineous Tunisian family with autosomal recessive nonsyndromic deafness, Tlili et al. (2005) identified a homozygous frameshift mutation in the WHRN gene (607928.0006) that segregated with the phenotype in the family.

Usher Syndrome Type IID

In 2 German sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383), Ebermann et al. (2007) identified compound heterozygosity for a nonsense (607928.0002) and a splice site mutation (607928.0003) in the WHRN gene. The authors noted that whereas mutations affecting the C-terminal half of whirlin have been reported in patients with nonsyndromic deafness (DFNB31), the alterations identified in this USH2 family both affect the long isoform of whirlin, suggesting that it is crucial for retinal function.

In 2 of 31 French USH2 patients who were not linked to the USH2A locus (608400), Besnard et al. (2012) identified homozygosity and compound heterozygosity for WHRN mutations, respectively (607928.0004; 607928.0005). Besnard et al. (2012) concluded that WHRN mutations account for a very small proportion of mutations causing USH2 (1.3%).


Animal Model

The 'whirler' mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicated that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair and outer hair cells. By BAC-mediated transgene correction of the mouse phenotype and mutation analysis, Mburu et al. (2003) identified the causative gene as encoding a PDZ protein they designated whirlin. They found that the same gene is mutant in the human autosomal recessive deafness locus DFNB31.


ALLELIC VARIANTS 6 Selected Examples):

.0001   DEAFNESS, AUTOSOMAL RECESSIVE 31

DFNB31, ARG778TER
SNP: rs137852839, gnomAD: rs137852839, ClinVar: RCV000002808, RCV001851590, RCV003226155

In affected members of a consanguineous Palestinian family with autosomal recessive nonsyndromic deafness mapping to chromosome 9q32-q34 (DFNB31; 607084), originally described by Mustapha et al. (2002), Mburu et al. (2003) identified a 2332C-T transition in exon 10 of the WHRN gene, resulting in an arg778-to-ter (R778X) substitution and a truncated protein of 777 amino acids lacking the third PDZ domain. The mutation was present in homozygous state in 6 affected members of the family and was either absent or present in heterozygous state in unaffected members of the family. The mutation was not found in 100 unrelated Jordanian individuals with normal hearing or in 150 probands from multiplex families with autosomal recessive forms of nonsyndromic deafness, indicating that this is a rare form of deafness.


.0002   USHER SYNDROME, TYPE IID

DFNB31, GLN103TER
SNP: rs137852840, gnomAD: rs137852840, ClinVar: RCV000002809

In 2 German sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383), Ebermann et al. (2007) identified compound heterozygosity for a 307C-T transition in exon 1 of the WHRN gene, resulting in a gln103-to-ter (Q103X) substitution, and a splice site mutation (837+1G-A; 607928.0003) in the donor site of intron 2, causing in-frame skipping of exon 2. The splice site mutation was predicted to result in an aberrant long isoform of whirlin lacking 73 residues (9 from PDZ1, the 53-residue linker region, and 11 from PDZ2). The mutations were not found in 100 healthy controls.


.0003   USHER SYNDROME, TYPE IID

DFNB31, IVS2DS, G-A, +1
SNP: rs2133130286, ClinVar: RCV000002810

For discussion of the splice site mutation in the WHRN gene (837+1G-A) that was found in compound heterozygous state in 2 sibs with mild congenital hearing loss, retinitis pigmentosa, and no vestibular dysfunction (USH2D; 611383) by Ebermann et al. (2007), see 607928.0002.


.0004   USHER SYNDROME, TYPE IID

DFNB31, 1-BP DEL, 737C
SNP: rs1589229634, ClinVar: RCV000024377, RCV003556086

In a patient with type II Usher syndrome (USH2D; 611383), Besnard et al. (2012) identified homozygosity for a 1-bp deletion (737delC) in exon 2 of the WHRN gene, causing a frameshift (Pro246fs) predicted to result in a premature termination codon. In an unrelated USH2 patient, Besnard et al. (2012) identified compound heterozygosity for 737delC and a 1-bp duplication (680dupG; 607928.0005) in exon 2 of the WHRN gene, also causing a frameshift (Tyr228fs) predicted to result in premature termination.


.0005   USHER SYNDROME, TYPE IID

DFNB31, 1-BP DUP, 680G
SNP: rs1306987034, gnomAD: rs1306987034, ClinVar: RCV000024378, RCV001852569

For discussion of the 1-bp duplication (680dupG) in the WHRN gene that was found in compound heterozygous state in a patient with type II Usher syndrome (USH2D; 611383) by Besnard et al. (2012), see 607928.0004.


.0006   DEAFNESS, AUTOSOMAL RECESSIVE 31

DFNB31, 1-BP DEL, 2423G
SNP: rs869320674, ClinVar: RCV000190401

By mutation screening of the WHRN gene in affected members of a Tunisian family with autosomal recessive nonsyndromic deafness showing linkage to the DFNB31 (607084) region, Tlili et al. (2005) identified homozygosity for a 1-bp deletion (c.2423delG, NM_015404.1), producing a frameshift and resulting in a premature stop codon (Gly808AspfsTer11 in the long isoform; Gly457AspfsTer11 in the short isoform). The deletion was found in heterozygous state in the unaffected parents and an unaffected sib.


REFERENCES

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Contributors:
Carol A. Bocchini - updated : 08/14/2015
Marla J. F. O'Neill - updated : 6/8/2012
Patricia A. Hartz - updated : 11/11/2009
Patricia A. Hartz - updated : 9/21/2009
George E. Tiller - updated : 12/11/2007
Marla J. F. O'Neill - updated : 8/21/2007
Patricia A. Hartz - updated : 10/3/2006
Patricia A. Hartz - updated : 5/20/2005
Victor A. McKusick - updated : 7/2/2003

Creation Date:
Patricia A. Hartz : 6/27/2003

Edit History:
carol : 10/11/2016
carol : 08/14/2015
carol : 8/13/2015
mcolton : 8/12/2015
terry : 6/8/2012
terry : 4/12/2012
alopez : 9/16/2011
terry : 9/9/2010
mgross : 11/16/2009
terry : 11/11/2009
mgross : 10/2/2009
terry : 9/21/2009
wwang : 12/28/2007
terry : 12/11/2007
wwang : 8/27/2007
terry : 8/21/2007
mgross : 10/5/2006
mgross : 10/5/2006
terry : 10/3/2006
wwang : 5/20/2005
alopez : 9/2/2003
alopez : 7/2/2003
terry : 7/2/2003
mgross : 6/30/2003