Alternative titles; symbols
HGNC Approved Gene Symbol: COL3A1
SNOMEDCT: 17025000; ICD10CM: Q79.63;
Cytogenetic location: 2q32.2 Genomic coordinates (GRCh38): 2:188,974,373-189,012,746 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2 | Ehlers-Danlos syndrome, vascular type | 130050 | Autosomal dominant | 3 |
| Polymicrogyria with or without vascular-type EDS | 618343 | Autosomal recessive | 3 |
Type III collagen is a fibrillar-forming collagen comprising 3 alpha-1(III) chains and is expressed in early embryos and throughout embryogenesis. In adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin (Liu et al., 1997).
Janeczko and Ramirez (1989) presented the nucleotide and amino acid sequences of type III collagen.
Jorgensen et al. (2015) noted that the fourth exon in the COL3A1 gene (residues 112 to 149 of the protein) appears to have fused the sequences equivalent to exons 4 and 5 in other fibrillar collagens. Thus, it is named exon 4/5 and the subsequent exon is designated exon 6.
Using a cloned gene as a probe on Southern blots of DNA from a panel of interspecies somatic cell hybrids, Solomon et al. (1985) assigned the COL3A1 gene to chromosome 2. Mudryj et al. (1985) independently assigned COL3A1 to chromosome 2q. Emanuel et al. (1985) concluded that both the alpha-1(III) and the alpha-2(V) procollagen genes map to chromosome 2q24.3-q31. To the time of this report, this was the only example of synteny of procollagen genes. By somatic cell hybrid studies and in situ hybridization, Huerre-Jeanpierre et al. (1986) assigned the COL3A1 gene to chromosome 2q31-q32.3.
Tsipouras et al. (1988) demonstrated that the COL3A1 and the COL5A2 (120190) genes are very close together; they found a maximum lod score of 9.33 at a recombination fraction of 0.00. Cutting et al. (1990) showed by pulsed field gel electrophoresis that the COL3A1 and COL5A2 genes are in the same 35 kb segment.
By fluorescence in situ hybridization, Limongi et al. (1997) concluded that the COL3A1 gene is located in chromosome band 2q32.2 and that the nebulin gene (161650) is located in band 2q24.2; the FRA2G fragile site was found to lie between the 2 genes in the 2q31 band.
Hartz (2013) mapped the COL3A1 gene to chromosome 2q32.2 based on an alignment of the COL3A1 sequence (GenBank M11134) with the genomic sequence (GRCh37).
To define the limits of the homologous segment between human chromosome 2 and proximal mouse chromosome 1, Schurr et al. (1990) determined the segregation of the mouse homologs of 7 human genes located on 2q with anchor loci on mouse chromosome 1. They concluded that COL3A1 and COL6A3 (120250) defined the limits of a homologous segment that in the mouse covers slightly more than 30 cM. They suggested that the order of loci in this segment of the mouse chromosome might be the same as the order in the human homolog.
Using synthetic triple-helical collagen-like peptides derived from the sequence of human and bovine type III collagen, Jarvis et al. (2008) identified several peptides that interacted with mouse and human GP VI (GP6; 605546). In particular, 1 peptide designated III-30 bound both mouse and human platelets in a GP VI-dependent manner. The III-30 peptide contained 3 hydroxyproline (O) residues within its OGP/GPO motifs, and modification of the III-30 peptide sequence indicated that these hydroxyproline residues played a significant role in supporting its GP VI reactivity, although motifs other than OGP/GPO contributed to the interaction.
Type III collagen serves as a ligand for the adhesion receptor GPR56 (ADGRG1; 604110). This interaction regulates the integrity of the pial basement membrane and cortical lamination in the brain, which is important for neuronal migration (summary by Vandervore et al., 2017).
Byers (1993) estimated that there are approximately 25 known mutations in the COL3A1 gene. These are divided about equally between point mutations that change a gly residue to another amino acid and exon skipping mutations. In the case of the COL1A1 gene, exon skipping mutations are much less frequent than point mutations. The COL3A1 gene also has an unusually high frequency of multi-exon deletions.
Van den Berg et al. (1998) studied the ratio of type III to type I collagen in fibroblast cultures from 16 patients with spontaneous cervical arterial dissections. Two of these patients had a low ratio of type III to type I, but no mutations in the type III collagen gene were detected by SSCP heteroduplex analysis.
Kuivaniemi et al. (1997) tabulated all reported disease-producing mutations in the COL3A1 gene.
Ehlers-Danlos Syndrome, Vascular Type
In 33 unrelated individuals or families with EDS type IV, the vascular type of EDS (EDSVASC; 130050), Schwarze et al. (1997) identified heterozygous mutations that affect splicing of the COL3A1 mRNA, of which 30 were point mutations at splice junctions and 3 were small deletions that removed splice-junction sequences and partial exon sequences. With the exception of 1 point mutation at a donor site, which led to partial intron inclusion, and a single-basepair substitution at an acceptor site, which gave rise to inclusion of the complete upstream intron into the mature mRNA, all mutations resulted in deletion of a single exon as the only splice alteration. Of the exon-skipping mutations that were due to single-base substitutions, which they had identified in 28 separate individuals, only 2 affected the splice-acceptor site. The underrepresentation of splice acceptor site mutations suggested to Schwarze et al. (1997) that the favored consequence of 3-prime mutations may be the use of an alternative acceptor site that creates a null allele with a premature termination codon. Phenotypes of these mutations may differ, with respect to either their severity or their symptomatic range, from the usual presentation of EDS type IV, and thus were excluded from the analysis.
Hamel et al. (1998) described 11 patients with a clinical phenotype consistent with the diagnosis of EDS and all with collagen III abnormalities. Collagen V appeared to be normal in all. The clinical diagnosis had been EDS II (see 130000), III (130020), or IV. There appeared to be no correlation between the type of collagen III anomaly and the clinical phenotype. Hamel et al. (1998) concluded that type III collagen abnormalities lead to a phenotypic spectrum and that it is impossible to predict severity and course of the disease from the biochemical defect.
Gilchrist et al. (1999) identified a gly571-to-ser mutation (120180.0026) in the COL3A1 gene in a large family with a milder phenotype than that typically associated with EDS type IV. They suggested that the nature of the substitution and its position may play a role in phenotype determination.
Pepin et al. (2000) determined the underlying COL3A1 mutation in 135 index patients with Ehlers-Danlos syndrome type IV. They found no association between types of complications and specific mutations in COL3A1. Four mutations led to the deletion of multiple exons, and 41 led to the skipping of a single exon. One mutation, ivs24+1G-A, led to the skipping of exon 24 in 7 unrelated index patients. In a total of 85 index patients, 73 different point mutations led to the substitution of some other amino acid for glycine in various regions of the triple-helical domain. A number of mutations--G16S (120180.0027) (7 families) and G82D (120180.0028), G373R (120180.0029), G385E (120180.0030), G415S (120180.0024), G499D (120180.0022), and G1021E (120180.0017) (2 families each)--were identified multiple times in unrelated index patients.
Mizuno et al. (2013) reported that EDS-associated mutations in the middle or close to the C terminus of COL3A1, including gly910 to val (120180.0010), significantly slowed the overall rate of triple-helix formation by COL3A1.
Polymicrogyria with or without Vascular-Type Ehlers-Danlos Syndrome
Plancke et al. (2009) reported an 11-year-old French girl, born of consanguineous parents, with polymicrogyria with vascular-type EDS (PMGEDSV; 618343), who was found to carry a homozygous truncating mutation in the COL3A1 gene (479dupT; 120180.0034). The patient's unaffected parents were each heterozygous for the mutation, suggesting autosomal recessive inheritance. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001), who reported a severe phenotype resulting from COL3A1 haploinsufficiency due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects.
In 2 sibs with PMGEDSV, Jorgensen et al. (2015) identified compound heterozygous mutations in the COL3A1 gene: a nonsense mutation (R596X; 120180.0035) and a substitution at a glycine residue (G1284E; 120180.0036). Patient fibroblasts showed a reduced amount of type III procollagen, the chains of which all had an abnormal electrophoretic mobility compared to controls, suggestive of overmodification of the protein possibly resulting from slow folding of the triple helical domain. Fibroblasts from the mother, who was heterozygous for the G1284E variant, showed a small amount of abnormal type III procollagen. The mother had subtle features of the disorder, including small joint hypermobility, aortic elasticity, emphysema, and thin, translucent skin. The father, who was heterozygous for the R596X variant, had no clinical features suggestive of EDS.
In a 3-year-old girl with PMGEDSV, Horn et al. (2017) identified compound heterozygous loss-of-function mutations in the COL3A1 gene (120180.0037 and 120180.0038). Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to cause nonsense-mediated mRNA decay and an inability to contribute to a triple helix, consistent with a complete loss of function. Each unaffected parent was heterozygous for 1 of the mutations.
In 2 sibs with polymicrogyria without vascular-type Ehlers-Danlos syndrome (PMGEDSV; 618343), who were born of unrelated parents from the same mountain village in Chechnya, Vandervore et al. (2017) identified a homozygous missense mutation in the COL3A1 gene (P49A; 120180.0039). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant is located in a von Willebrand factor C domain that may mediate interaction with GPR56 (604110) in the N terminus of the pro-COL3A1 chain; this region is usually cleaved from the intact type III collagen domain. Patient fibroblasts showed increased levels of COL3A1 mRNA, but normal amounts of the COL3A1 protein. Immunoprecipitation assays showed no significant differences in the COL3A1 interaction with GPR56, although there was a slight alteration of binding capacity. Vandervore et al. (2017) suggested that there may be tissue-specific effects of the mutation that may result in overstimulation of neuronal migration, or that the mutation may cause altered signaling patterns involved in pial basement membrane assembly.
Horn et al. (2017) identified the same homozygous P49A mutation in 2 sibs, born of unrelated parents from Chechnya and Ingushetia, with polymicrogyria without vascular-type Ehlers-Danlos syndrome. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic or likely pathogenic according to ACMG criteria.
Schwarze et al. (2001) studied 4 patients with EDS IV who presented with vascular aneurysm or rupture and were found to be haploinsufficient for a COL3A1 allele. They found 3 frameshift mutations that resulted in premature termination codons in exons 27, 6, and 9, and to allele-product instability. The fourth patient was found to have a termination point mutation in the final exon that resulted in a stable mRNA product but led to the synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. Schwarze et al. (2001) noted that in contrast to the severe phenotype in these patients, mice that are haploinsufficient for COL3A1 have no identified phenotype and individuals with null mutations in the dominant protein of a tissue, i.e., COL1A1 and COL2A1, have milder phenotypes than those caused by mutations that alter protein sequence. Schwarze et al. (2001) suggested that the major effect of many of these dominant mutations in the 'minor' collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.
To study directly the role of COL3A1 in development and disease, Liu et al. (1997) inactivated the murine Col3a1 gene in embryonic stem cells by homologous recombination. The mutated allele was transmitted through the mouse germline and homozygous mutant animals were derived from heterozygous intercrosses. Heterozygous mice were phenotypically normal. However, about 10% of the homozygous mutant animals survived to adulthood but had a much shorter life span compared with wildtype mice. The major cause of death in mutant mice was rupture of the major blood vessels, similar to patients with type IV Ehlers-Danlos syndrome. Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs.
Jeong et al. (2012) found that homozygous Col3a1-null mice had a cobblestone-like cortical malformation with breakdown of the pial basement membrane and marginal zone heterotopias. There was also neuronal overmigration and radial glial detachment. The defects started around embryonic day 11.5. The findings indicated an important role for collagen III in the developing brain.
In a patient with type IV Ehlers-Danlos syndrome (EDSVASC; 130050), Tromp et al. (1989) found a heterozygous substitution of serine for glycine-790 in type III collagen. The mutation probably made the procollagen molecule unusually sensitive to proteases because it caused local unfolding of the triple helix and exposed the adjacent arginine residue. This patient had been thought to carry an amino acid insertion because of the slower migration of the pro-alpha chains of type III collagen (Stolle et al., 1985). The clinical features were reported by Pyeritz et al. (1984); the 16-year-old man presented with a right neck mass that developed suddenly at age 14 after forceful spitting and was shown by angiography to be an aneurysm arising at the origin of the right subclavian. His father died after several operations for spontaneous massive intraabdominal hemorrhage. His aunt died of a rent in the abdominal aorta that occurred spontaneously in the first stage of labor. His uncle required colostomy after spontaneous rupture of the bowel and died several years later of spontaneous rupture of the splenic artery.
In a 37-year-old female captain in the U. S. Air Force who was studied because several relatives had died of ruptured aortic aneurysms (see EDSVASC; 130050), Kontusaari et al. (1990) found heterozygosity for a single base mutation that converted the codon for glycine-619 in type III procollagen to arginine. The collagen produced had decreased temperature for thermal unfolding. The same mutation was found in DNA extracted from pathologic specimens from her mother, who had died at the age of 34 of aortic aneurysm, and a maternal aunt, who died at the age of 55 of the same cause. DNA from samples of saliva showed that the woman's daughter, son, brother, and an aunt also had the mutation. Kuivaniemi et al. (1991) described the same family in brief. The proband had a tendency to bruise easily, and the surgeon who had previously removed her appendix noted that her tissues seemed friable and bled easily, with the loss of 1 liter of blood during that operation.
In a father and daughter with Ehlers-Danlos syndrome type IV (EDSVASC; 130050), Tromp et al. (1989) identified a G-to-A transition in the COL3A1 gene, resulting in a gly883-to-asp (G883D) substitution.
In a 34-year-old man with a history of thin skin and easy bruisability, who died of massive intrathoracic and intraabdominal hemorrhage (see EDSVASC; 130050), Kontusaari et al. (1990) identified heterozygosity for a substitution of A for G at the first nucleotide of intron 20 in the COL3A1 gene. As a result, the consensus sequence of GT found in most of the introns of eukaryotic genes was converted to AT. At autopsy, no distinct aneurysm or bleeding point was identified, but microscopic sections of aorta revealed an apparent decrease in and disorganization of elastic fibers, and all the abdominal soft tissues appeared to be unusually friable. The proband's father and 1 brother had died of rupture of abdominal and thoracic aneurysms, respectively.
In a patient with type IV EDS (EDSVASC; 130050), Kuivaniemi et al. (1990) found a G(+1)-to-A mutation in intron 16, which caused extensive exon skipping. The patient was a 36-year-old pregnant woman who had thin skin with abnormally prominent superficial blood vessels. She had a minimal degree of joint hypermobility and a history of 2 surgical procedures for correction of patellar dislocations. Cesarean section was performed because of premature ruptured membranes. The infant developed severe bleeding and died 4 hours later. The patient's tissues appeared to be unusually friable at surgery. The only other affected relative was a brother who died at the age of 20 of a ruptured cervical artery sustained during karate practice.
Kuivaniemi et al. (1990) found that a G-to-A mutation at the first nucleotide in intron 42 caused deficient use of a single cryptic splice site. The patient was a 22-year-old woman who died suddenly from a ruptured dissecting aortic aneurysm. She had thin and transparent skin with abnormally prominent blood vessels. She had mild hypermobility of the joints, congenital dislocation of the hips, and a torn knee ligament. She had a history of bouts of abdominal pain and urinary tract infections as well as pyloric stenosis in infancy. There was no evidence of EDS in other members of the family, including an 11-month-old daughter.
Zafarullah et al. (1990) demonstrated a change from GCT (ala) to ACT (thr) in the codon for amino acid 531 of the triple helix. On the basis of a study of 122 chromosomes, the frequency of the alanine allele was 0.68.
Wu et al. (1993) identified a G-to-T transversion at the fifth nucleotide of intron 37 of the COL3A1 gene from a woman with EDS4 (EDSVASC; 130050) who had died suddenly of rupture of a thoracic aorta in the age of 47.
In a patient with severe EDS IV (EDSVASC; 130050), Superti-Furga et al. (1988) showed that fibroblasts synthesized normal-sized and shortened type III procollagen chains. Comparison of the triple-helical domains of these 2 peptides and coarse Southern blot analysis of the patient's DNA suggested a large deletion in the middle portion of the COL3A1 gene. Lee et al. (1991) showed that the structural defect resulted from exon-to-intron recombination that deleted 16 exons of the triple-helical coding domain of COL3A1, removing about 7.5 kb and 1,026 nucleotides of coding sequence from the message. The deleted segment extended from the thirteenth nucleotide of exon 9 to within a DNA sequence of intron 24, which is composed of a series of dinucleotide repeats. Using PCR, Lee et al. (1991) tested the polymorphic nature of this dinucleotide repeat. At least 4 distinct allelic forms were found.
Richards et al. (1991) found a G-to-T mutation in the COL3A1 gene, resulting in a substitution of glycine-910 by valine. Nuytinck et al. (1992) described the patient and laboratory findings in detail. A 54-year-old woman had a lifetime history of easy bruising and recurrent bleeding and hematomas. She had varicose veins of the legs and attacks of superficial phlebitis. On 3 occasions her right shoulder had dislocated spontaneously. Family history was negative. She was only 149 cm tall and had facial features strongly suggestive of EDS IV (EDSVASC; 130050), including prominent eyes with bluish sclerae, a pinched nose, and hypoplastic earlobes. The skin was generally thin and showed a prominent venous pattern but was not hyperextensible. The knees and shins showed atrophic scars and hemosiderin deposits at the sites of old hematomas. There was hyperextensibility of large joints, especially the elbows and knees, but mobility of small joints was within normal limits. At the age of 54 years she developed a perforation of the sigmoid colon for which a sigmoidectomy was performed. The patient's skin fibroblasts produced markedly diminished amounts of type III collagen. Cells obtained from noncutaneous tissues showed 2 forms of type III chains, one normal and one slow migrating. The type III collagen molecules containing mutant alpha chains were overmodified, had a lower thermal stability, and were poorly secreted into the extracellular medium. Nuytinck et al. (1992) pointed out that the mutant molecules were preferentially retained within cultured cells, presumably destined for degradation. By reducing the incubation temperature of the cells, the secretion of type III collagen was increased considerably. For this reason, cooler superficial tissues, such as skin, may be less dramatically affected than internal organs.
In a sporadic case of EDS IV (EDSVASC; 130050), Lee et al. (1991) demonstrated a G-to-T transversion at position 5 of the splice donor site of intron 25 in one of the patient's COL3A1 genes. The splicing mutation resulted in skipping of exon 25. As in previously characterized splicing mutations in other collagen genes, lowering the temperature at which the patient's fibroblasts were incubated nearly abolished exon skipping. The mutation was first localized by amplifying the reverse transcribed product in several overlapping fragments by use of PCR. Amplified products spanning exon 24-26 sequences displayed 2 distinct fragments, one of normal size and the other lacking the 99 basepairs of exon 25. As part of the study, Lee et al. (1991) identified a highly polymorphic, intronic DNA sequence whose different allelic forms could be easily detected by the PCR technique.
The patient studied by Lee et al. (1991) had suffered since boyhood from easy bruising and episodes of hemorrhage occurring spontaneously or after trivial trauma. Physical examination at age 31 years showed thin, delicate skin with hemosiderotic, atrophic scars as well as paradoxically striking keloids. Superficial veins were easily visible and flexion contractures of the thumb and third finger of the right hand were found. He also had partial right bundle branch block and pulmonary stenosis (confirmed by angiography at age 19 years). He died at age 32 after falling from a bar stool.
Sillence et al. (1991) described the clinical features in a patient with EDS IV (EDSVASC; 130050) in whom Cole et al. (1990) found heterozygosity for a G-to-A transition at the splice donor site of intron 41. The mutation resulted in the splicing out of exon 41, which encoded 36 amino acids from glycine-775 to lysine-810 of the triple helical domain of type III collagen. The amount of type III collagen in the dermis was only about 11% of normal. The patient had typical features of the acrogeric form of EDS IV: characteristic facies with pinched nose and thin lips, aesthenic build, thin skin, prominent subcutaneous veins, and senile-appearing hands. Spontaneous bruising, bleeding from the large bowel, constipation, and delayed gastric emptying were other features.
Matton et al. (1982) described a large Belgian family with EDS IV (EDSVASC; 130050) in which Nicholls et al. (1988) showed that the abnormal phenotype was linked to an AvaII polymorphism in the COL3A1. In contrast to most EDS IV patients, fibroblasts from affected members of this family secreted nearly normal amounts of an apparently normal collagen. Although the level of type III collagen secreted was slightly lower than that secreted by control cell lines, the level of COL3A1 mRNA was normal. Richards et al. (1992) localized the mutation in this family to the CB5 peptide of type III collagen by use of both protein and cDNA mapping techniques. Sequence analysis of cDNA demonstrated a 27-bp deletion within exon 37, removing 9 amino acids and maintaining the Gly-X-Y repeat of the collagen helix. Further studies showed that the deletion was present in all affected members and absent in all unaffected members of the kindred. The deletion was flanked by 2 short direct repeats of CTCC; it appeared to have arisen by slipped mispairing.
In 3 affected members of the family of the patient with spontaneous carotid-cavernous fistula reported by Fox et al. (1988), Richards et al. (1992) demonstrated a G-to-A mutation converting glycine-847 to glutamic acid. The spontaneous carotid-cavernous fistula was successfully embolized and occluded. The mother and only sib had thin skin and joint laxity. The mother died at the age of 50 years from postoperative complications following ruptured bowel. Richards et al. (1992) showed that the mutation must have arisen during embryogenesis of the proband's maternal grandmother who was clinically unaffected but mosaic for the mutation.
In a 41-year-old woman with arterial ruptures and skin changes characteristic of type IV Ehlers-Danlos syndrome (EDSVASC; 130050), Kontusaari et al. (1992) found a single base substitution in the COL3A1 gene which converted the codon for glycine at amino acid position 1018 to a codon for aspartate. (Amino acid positions were numbered by the convention in which the first glycine of the triple-helical domain of an alpha chain is numbered 1. The number of positions in the mature collagen chain can be converted to positions in the procollagen chain by adding 167.) The glycine mutation markedly decreased the amount of type III procollagen secreted into the medium by cultured skin fibroblasts. The same mutation was found in about 94% of peripheral blood leukocytes of the proband's asymptomatic 72-year-old mother. The mutation was present in 0.0-100% of different samples of hair cells and in about 40% of cells from the oral epithelium. Since the mutated allele was present in cells derived from all 3 germ layers, the results indicated that the mutation arose by the late blastocyst stage of development. The proband had been born prematurely without obvious cause. Her case was reported by Morris (1957) as one of acrogeria; her hands and feet were described as 'emaciated and fleshless with the veins showing through the thin and wrinkled skin.' At the age of 24 years, she had spontaneous rupture of the splenic artery. Two years later she developed recurrent pneumothoraces. At age 28 she had a perinephric hematoma requiring left nephrectomy for control of bleeding. At age 39 a large spontaneous hematoma in her left thigh was thought to represent a venous rupture. The mother had no history of easy bruisability or hemorrhaging and her skin was normal on examination by Morris (1957) and by one of the authors (F.M.P.) in the Kontusaari et al. (1992) report (Pope et al., 1980).
Using denaturing gradient gel electrophoresis (DGGE), Johnson et al. (1992) identified heterozygosity for a GGA-to-GAA transition in codon 1006 creating a new HinfI restriction site and substitution of glutamic acid for glycine at residue 1006 of the COL3A1 chain. The patient had typical acrogeric EDS IV (EDSVASC; 130050) and had been reported by Roberts et al. (1984) as mimicking nonaccidental injury, i.e., child abuse.
Narcisi et al. (1993) described a 24-year-old woman with type IV Ehlers-Danlos syndrome (EDSVASC; 130050) and sudden death due to 'massive' aortic dissection arising about 0.5 cm above the aortic ring and extending to the aortic bifurcation. The aneurysm had ruptured through the left lateral wall of the abdominal aorta, producing a large retroperitoneal hemorrhage. The presence of atrophy of all finger pulps with acroosteolysis and loss of the first and second fingernails on the left hand were commented on. Narcisi et al. (1993) found a single base mutation in exon 49 of the COL3A1 gene which caused a gly-to-glu substitution at amino acid residue 1021.
Pepin et al. (2000) found the G1021E mutation in 2 of 135 unrelated EDS IV families.
In a large study involving sequencing of cDNA for the triple-helical domain of type III procollagen in 54 patients with aortic aneurysms, Tromp et al. (1993) found only one with a mutation of likely functional significance: a substitution of arginine for an obligatory glycine at amino acid position 136. The nucleotide change was a transition from GGG to AGG at position 907. The patient was an 18-year-old black male without any prior relevant medical history. He had suddenly developed paraparesis and bilateral loss of pulses below the waist (Gatalica et al., 1992). An aortogram disclosed a dissecting aneurysm of the entire aorta and obstruction of blood flow below the renal arteries. Autopsy demonstrated the dissecting aneurysm and generalized fibromuscular dysplasia (135580). His father had died at the age of 36 years in a car accident and no affected relatives were available for DNA testing. His mother did not have the mutation, but 3 unaffected sibs were found to have the same mutation. Ultrasound examination of the aorta in these sibs, aged 21, 20, and 16 years, did not reveal any abnormalities.
Byers (1998) was of the opinion that the patient with the G136R mutation in COL3A1 actually represented an example of EDS type IV (EDSVASC; 130050). Schievink and Limburg (1989) described a 46-year-old woman with Ehlers-Danlos syndrome type IV who suffered an aneurysmal subarachnoid hemorrhage. Angiographic abnormalities in the carotid arteries resembling fibromuscular dysplasia were described. In an angiographic study of the cervical arteries in 102 patients with aneurysmal subarachnoid hemorrhage, George et al. (1989) found arterial wall irregularities consistent with fibromuscular dysplasia in 29 patients, coiling or kinking in 21 patients, and a combination of both angiographic abnormalities in an additional 7 patients.
In a 32-year-old woman with type IV EDS (EDSVASC; 130050), Lloyd et al. (1993) identified a T-to-C transition at nucleotide +6 in the donor splice site of IVS7 of the COL3A1 gene. This resulted in skipping of exon 7, which is the most 5-prime of the completely triple helix encoding exons, since exon 6 of the COL3A1 gene codes partially for the N-peptidase cleavage site and the first 9 amino acids of the triple helix. The patient, who suffered from a de novo mutation, was classified as having a nonacrogeric form of this disorder. She came to medical attention because of infection of the right kidney and intermittent claudication of the left leg. Angiography showed occlusion of the right renal artery and stenosis of the left iliac artery with possible dissection. Four years previously she suffered perforation of the bowel and had varicose veins since her teens.
Narcisi et al. (1994) described a family in which the proband was a 4-year-old boy with generalized joint laxity and minor skin extensibility without scarring. Four other members of the family were affected: his 36-year-old father, a younger brother, a 39-year-old paternal uncle, and the 64-year-old paternal grandmother. The disorder in the family was diagnosed as EDS III (130020)/articular hypermobility syndrome (147900); the latter is not clearly distinguished from EDS III. Analysis of cultured fibroblasts from the affected members demonstrated intracellular retention of type III collagen. This is usually a biochemical characteristic of EDS IV (130050), caused by mutations of COL3A1. Analysis of the cDNA sequence in this family revealed a glycine-to-serine mutation at amino acid residue 637 of the type III collagen molecule. This was confirmed by allele-specific oligonucleotide hybridization against amplified genomic DNA. There was no history of vascular fragility in the family and there were no other clinical signs usually associated with EDS IV such as thin skin and characteristic facial features.
Thakker-Varia et al. (1995) identified a unique mutation in the COL3A1 gene in a 22-year-old woman who was the only 1 of 5 sibs affected by type IV EDS (EDSVASC; 130050). Her mother died at age 35 from a massive abdominal hemorrhage after a minor car accident and was probably affected. During delivery of a seemingly unaffected daughter, the proband experienced protracted bleeding and significant tear damage of the pelvic tissues. The skin was soft and hyperextensible around the elbows, but not on the upper thorax, where it was thin and translucent. No evident joint hypermobility was noted, while marked, diffuse bruising and pigmented scars were present. The facies was characteristic, with a thin nose, thin lips, and fine wrinkles around the mouth. The patient's fibroblasts produced decreased amounts of type III procollagen despite normal levels of translatable type III procollagen mRNA. S1 nuclease analysis of the type III procollagen mRNA indicated a defect in the region encoding exon 27. Sequence analysis of cDNA clones and genomic fragments generated by PCR amplification demonstrated that sequences representing exon 27 were absent from 3 out of 5 cDNA clones and that a G at the +5 position of the splice donor site in intron 27 was changed to an A in 1 allele of their patient's COLA3A1 gene. Thakker-Varia et al. (1995) could demonstrate that mRNA species containing and lacking exon 27 were produced in a 1:1 ratio. However, pulse label and chase experiments in the presence or absence of brefeldin A indicated that most of the type III procollagen molecules synthesized by the patient's fibroblasts were not secreted into the medium but were degraded in the endoplasmic reticulum-Golgi compartment by a nonlysosomal mechanism.
McGrory et al. (1996) found heterozygosity for a G-to-A transition at nucleotide 1997, resulting in a G499D substitution in type III collagen in a 48-year-old man with the acrogeric form of type IV EDS (EDSVASC; 130050). The patient had been reported by Pope et al. (1988). The age of onset of his acrogeric appearance was uncertain, but with increasing age it had become more severe. At 49 years of age, he died from massive pulmonary emboli and acute myocardial infarction. The man had only 1 son who was clinically normal at 15 years of age. However, he showed heterozygosity for the same mutation.
Pepin et al. (2000) found the G499D mutation in 2 of 135 unrelated EDS IV families.
Tromp et al. (1995) found a G-to-T transition at position 2879 (exon 41) in the COL3A1 gene that changed the codon for glycine-793 to a codon for valine in a mother and her son with Ehlers-Danlos syndrome type IV (EDSVASC; 130050). Clinical details of this family were reported by De Paepe et al. (1989). This substitution most likely disrupted the triple-helical structure of the protein and made it less stable.
Anderson et al. (1997) stated that more than 40 mutations in the type III procollagen gene had been described in patients with EDS IV (EDSVASC; 130050). These mutations included missense mutations, splice site mutations, and deletions. They reported a G-to-A transition that altered codon 415 from GGT (glycine) to AGT (serine). They stated that the mutation results in impaired secretion and decreased thermal stability type III procollagen.
Pepin et al. (2000) found the G415S mutation in 2 of 135 unrelated EDS IV families.
McGrory et al. (1996) found a 3302G-A transition in exon 46 of the COL3A1 cDNA resulting in a gly934-to-glu substitution. The mutation resulted in a severe deficiency of type III collagen in fibroblast cultures and dermis. Dilatation of the endoplasmic reticulum of the dermal fibroblast was probably due to failure of these cells to secrete type III collagen molecules containing one or more mutant alpha-1(III) chains. The dermal collagen fibrils were narrow, but their constituent type III collagen molecules contained predominantly normal alpha-1(III) chains. As a result, the major effect of the mutation was to reduce severely the amount of normal type III collagen available for the formation of collagen fibrils in the extracellular matrix. The 50-year-old patient studied by McGrory et al. (1996) had hypermobile joints with recurrent dislocations of the shoulders, thumbs, and patellae, skin laxity, and easy bruising. At the age of 28 she had an aortic thrombosis and at 50 she developed proptosis and was shown to have carotico-cavernous fistulae and dilatations of the internal carotid and vertebral arteries. Her sister had similar cutaneous and joint anomalies, and had a myocardial infarction at 34 years of age. The proband's mother, aged 78 years, had joint hypermobility and skin laxity suggestive of EDS IV (EDSVASC; 130050).
In a large kindred with EDS type IV (EDSVASC; 130050) in which 15 members were affected in 4 generations, Gilchrist et al. (1999) identified a G-to-A transition that resulted in a gly571-to-ser substitution in the triple helical domain of the products of one COL3A1 allele. This family had a milder phenotype than that typically associated with EDS IV. Clinical presentation in some of the affected members occurred at a later age than usual. Longevity was longer than that seen in many families, and there was less pregnancy-associated morbidity or mortality than that found in some families. The authors suggested that some clinical aspects of EDS IV may be related to the nature of the mutation and its effect on the behavior of the protein.
In 7 of 135 unrelated families, Pepin et al. (2000) found a gly16-to-ser mutation in the COL3A1 gene as the cause of type IV EDS (EDSVASC; 130050).
In 2 of 135 unrelated families, Pepin et al. (2000) found a gly82-to-asp mutation in the COL3A1 gene as the cause of type IV EDS (EDSVASC; 130050).
In 2 of 135 unrelated families, Pepin et al. (2000) found a gly373-to-arg mutation in the COL3A1 gene as the cause of type IV EDS (EDSVASC; 130050).
In 2 of 135 unrelated families, Pepin et al. (2000) found a gly385-to-glu mutation in the COL3A1 gene as the cause of type IV EDS (EDSVASC; 130050).
In a mother and son with EDS type IV (EDSVASC; 130050) and unusual congenital anomalies, Kroes et al. (2003) identified an 889G-A transition in the COL3A1 gene, resulting in a gly297-to-arg (G297R) substitution. The mother had amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephalus; the son had esophageal atresia and hydrocephalus. The patients were also anomalous in that protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities. Kroes et al. (2003) referred to another patient in which the collagen profile was normal on electrophoresis but a pathogenic mutation was identified (120180.0032). In that case also the phenotype was atypical and the mutation was located relatively near the N terminus of the protein. (The numbering originally used by Kroes et al. (2003) started at the collagen part of the gene, with the first glycine codon of the triple helix, and the mutation was stated to be a 388G-A transition resulting in a GLY130ARG (G130R) substitution.)
Pinto et al. (2000) described a splice site mutation in the COL3A1 gene (IVS8+5G-A) in a 40-year-old man who did not show the classic phenotype of EDS IV (EDSVASC; 130050). He had no skin or joint abnormalities. Examination showed necrotic degeneration in vascular walls, aneurysms, and medial degeneration in several tissues. Another notable feature was the finding of a normal collagen profile on electrophoresis, despite the DNA abnormality. The patient had a history of bilateral renal-artery stenosis and spontaneous hematothorax. Laparotomy for possible appendicitis revealed a pulseless ileocolic artery and an ischemic colon. Resection of ischemic intestine was performed on 2 successive days; on the third day laparotomy revealed a ruptured abdominal aorta (from which the patient ultimately died) and 6 days later laparotomy revealed a ruptured gallbladder.
Byers et al. (2000) stated that their series of patients with EDS IV included 2 with the IVS8+5G-A mutation.
In a 24-year-old woman with atypical features of EDS type IV (EDSVASC; 130050) and her mother, Palmeri et al. (2003) identified a 3149G-T transversion in exon 44 of the COL3A1 gene, resulting in a gly883-to-val (G883V) mutation. The phenotypically normal maternal grandmother was found to be mosaic for this mutation. The proposita suffered from chronic pain in the legs and progressive retraction of her left Achilles tendon causing talipes equinovarus. She had suffered from painful nocturnal cramps of both legs since the age of 10 years. She had an acrogeric face and flexion contractures of the interphalangeal joints of the fourth and fifth fingers. The muscular features were initially considered suggestive of distal X-linked arthrogryposis multiplex congenita (301830). The mother suffered an ischemic stroke at the age of 43 years and died suddenly at the age of 48 years. A sister of the mother died at the age of 40 years of a ruptured abdominal aortic aneurysm.
In a 11-year-old French girl, born of consanguineous parents, with polymicrogyria with vascular-type EDS (PMGEDSV; 618343), Plancke et al. (2009) identified a homozygous 1-bp duplication (c.479dupT) in exon 5 of the COL3A1 gene, resulting in a frameshift and premature termination (Lys161GlnfsTer45). The transmission pattern was consistent with autosomal recessive inheritance. She had thin, translucent skin with marked scars, early-onset varicose veins, hypermobility of the small joints, gingival recession, hypoplastic nasal alae, and think lips. She also had delayed motor development, absence epilepsy, and diffuse cortical dysplasia. She presented with acute abdominal pain, and surgery revealed extreme intestinal, arterial, and tissue fragility. She died after surgery from multiple perforations, suture breakdown, and total evisceration. The patient's unaffected parents were each heterozygous for the mutation. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001), who reported a severe phenotype resulting from COL3A1 haploinsufficiency due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects.
In 2 sibs, with polymicrogyria with vascular-type EDS (PMGEDSV; 618343), Jorgensen et al. (2015) identified compound heterozygous mutations in the COL3A1 gene: a c.1786C-T transition in exon 26, resulting in an arg596-to-ter (R596X) substitution, and a c.3851G-A transition in exon 50, resulting in a gly1284-to-glu (G1284E; 120180.0036) substitution at a highly conserved residue in a triple helical domain. The c.1786C-T variant was predicted to result in nonsense-mediated mRNA decay and a null allele. Patient fibroblasts showed a reduced amount of type III procollagen, the chains of which all had an abnormal electrophoretic mobility compared to controls, suggestive of overmodification of the protein possibly resulting from slow folding of the triple helical domain. Fibroblasts from the mother, who was heterozygous for the G1284E variant, showed a small amount of abnormal type III procollagen. The mother had subtle features of the disorder, including small joint hypermobility, aortic elasticity, emphysema, and thin, translucent skin. The father, who was heterozygous for the R596X variant, had no clinical features suggestive of EDS.
For discussion of the c.3851G-A transition in exon 50 of the COL3A1 gene, resulting in a gly1284-to-glu (G1284E) substitution, that was found in compound heterozygous state in 2 sibs with polymicrogyria with vascular-type EDS (PMGEDSV; 618343) by Jorgensen et al. (2015), see 120180.0035.
In a 3-year-old girl with polymicrogyria with vascular-type EDS (PMGEDSV; 618343), Horn et al. (2017) identified compound heterozygous mutations in the COL3A1 gene: a c.1281C-T transition (c.1281C-T, NM_000090.3) in exon 19, resulting in an arg428-to-ter (R428X) substitution, and a 1-bp deletion (c.2057delC; 120180.0038) in exon 31, resulting in a frameshift and premature termination (Pro686LeufsTer105). Neither variant was found in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to cause nonsense-mediated mRNA decay and an inability to contribute to a triple helix, consistent with a complete loss of function. Each unaffected parent was heterozygous for 1 of the mutations.
For discussion of the 1-bp deletion (c.2057delC, NM_000090.3) in the COL3A1 gene, resulting in a frameshift and premature termination (Pro686LeufsTer105), that was found in compound heterozygous state in a patient with polymicrogyria with vascular-type EDS (PMGEDSV; 618343) by Horn et al. (2017), see 120180.0037.
In 2 sibs with polymicrogyria without vascular-type Ehlers-Danlos syndrome (PMGEDSV; 618343), who were born of unrelated parents from the same mountain village in Chechnya, Vandervore et al. (2017) identified a homozygous c.145C-G transversion (c.145C-G, NM_000090.3) in exon 2 of the COL3A1 gene, resulting in a pro49-to-ala (P49A) substitution at a highly conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP or ExAC databases. The variant is located in a von Willebrand factor C domain that may mediate interaction with GPR56 (604110) in the N terminus of the pro-COL3A1 chain; this region is usually cleaved from the intact type III collagen domain. Patient fibroblasts showed increased levels of COL3A1 mRNA, but normal amounts of the COL3A1 protein. Immunoprecipitation assays showed no significant differences in the COL3A1 interaction with GPR56, although there was a slight alteration of binding capacity. Vandervore et al. (2017) suggested that there may be tissue-specific effects of the mutation that result in overstimulation of neuronal migration, or that the mutation may cause altered signaling patterns involved in pial basement membrane assembly.
Horn et al. (2017) identified the same homozygous P49A mutation in 2 sibs, born of unrelated parents from Chechnya and Ingushetia, with polymicrogyria without vascular-type Ehlers-Danlos syndrome. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic or likely pathogenic according to ACMG criteria.
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