Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome

Hout, Annemarie H. van der; Verlind, E; Beemer, Frits A.; Buys, Charles H.C.M.; Hofstra, Robert; Scheffer, Hans

doi:10.1002/humu.9061

Cited by 16 publications

(17 citation statements)

References 10 publications

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“…This panel of 77 different mutations included 1 deletion of the entire gene, 19 13 nonsense mutations, 21 deletions, 1 insertion, 9 duplications, 2 combinations of an insertion and a deletion, 22 splice site alterations, 1 synonymous mutation, 2 missense mutations resulting in an arginine-to-cysteine substitution 20 and 5 missense mutations substituting a glycine residue in the triple helical domain of the protein. The mutations were distributed over the entire gene and no hot spot regions were apparent (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

et al. 2010

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Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (Po0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as 490% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

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Section: Resultsmentioning

confidence: 99%

“…15 The probe set for COL2A1 (SALSA MLPA kit P214) covering exons 1,4,6,8,10,16,17,19,20,24,27,29,31,35,39,43,46, 49, 51 and 54 was used.…”

Section: Mlpa Analysismentioning

confidence: 99%

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

et al. 2010

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“…Deletions of the entire COL2A1 gene and its boundaries have been previously published. [19][20][21][22] The second large (10.554 bp) deletion, p.(Gln29Argfs*35), c.85+1360_1023 +555del, was identified in a Stickler proband and his affected father. Both patients displayed severe myopia, and the proband also had bilateral retinal detachment and skeletal anomalies.…”

Section: Discussionmentioning

confidence: 99%

“…23 These two deletions, which were both identified in Stickler cases, were also predicted to be subjected to NMD like the smaller rearrangement described above and would result in a haploinsufficiency. 19 The third large deletion was an in-frame deletion p.(Pro916_Gly1074del), c.2745_3221del, that was expected to result in a shortened peptide lacking 159 amino acids that would exert a dominant negative effect on the 'healthy' component of the trimeric collagen. This hypothesis might account for the severe phenotype observed in this lethal achondrogenesis, type II case.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular defects in the COL2A1 gene (MIM#108300), which encodes the alpha 1 chain of procollagen type II, result in skeletal, 12 Service de Génétique, CHU Félix Guyon, Saint-Denis, La Réunion, France; 13 Service de Génétique, CHU de Nancy, Nancy, France; 14 Génétique Médicale, CHU, Nantes, France; 15 Service de Biologie du Développement, Hôpital Robert Debré, Paris, France; 16 Centre de Génétique, CHU Dijon -Hôpital d'Enfants, Dijon, France; 17 Département de Génétique Médicale, CHU de Nice -Hôpital de l'Archet II, Nice, France; 18 Unité de Génétique Clinique, CHU de Rouen -Hôpital Charles Nicolle, Rouen, France; 19 Génétique Médicale, CHU de la Réunion, Saint Pierre, La Réunion, France; 20 orofacial, and ocular disorders. These dominantly inherited diseases are associated with various COL2A1 variants that include missense, nonsense, small indels or large deletions.…”

Section: Introductionmentioning

confidence: 99%

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The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Barat‐Houari

Dumont²,

Fabre³

et al. 2015

Eur J Hum Genet

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Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

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Spondyloperipheral dysplasia is caused by truncating mutations in the C‐propeptide of COL2A1

Zankl

Zabel²,

Hilbert³

et al. 2004

American J of Med Genetics Pt A

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The term "spondyloperipheral dysplasia" (SPD) has been applied to the unusual combination of platyspondyly and brachydactyly as observed in a small number of individuals. The reported cases show wide clinical variability and the nosologic status and spectrum of this condition are still ill defined. Zabel et al. [1996: Am J Med Genet 63(1):123-128] reported an individual with short stature and SPD who was heterozygous for a frameshift mutation in the C-propeptide domain of COL2A1. To explain the additional finding of brachydactyly that is not an usual feature of the type II collagenopathies, it was postulated that the nature of the mutation induced precocious calcification and premature fusion of metacarpal and phalangeal growth plates. The C-propeptide of collagen II had previously been found to promote calcification ("chondrocalcin"). We have ascertained two further individuals with clinical and radiological findings of a type II collagenopathy in infancy who developed brachydactyly type E like changes of fingers and toes in childhood. In both individuals, heterozygosity for novel, distinct mutations in the C-propeptide coding region of COL2A1 were found. Although all three mutations (the one previously reported and the two novel ones) predict premature termination, their location close to the 3'-end of the mRNA probably protects them from nonsense-mediated decay and allows for synthesis of mutant procollagen chains. However, loss of crucial cysteine residues or other sequences essential for trimerization prevents these chains from associating and participating in procollagen helix formation, and thus leads to accumulation in the ER-consistent with EM findings. The mechanism leading to precocious fusion of phalangeal epiphyses remains to be explored. The consistency of clinical, radiographic, and molecular findings in these three unrelated individuals confirms SPD as a distinct nosologic entity. The diagnosis of SPD is suggested by the appearance of brachydactyly in a child who has clinical and radiographic features of a collagen II disorder.

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Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome

Cited by 16 publications

References 10 publications

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

Spondyloperipheral dysplasia is caused by truncating mutations in the C‐propeptide of COL2A1

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