A Heterozygous Mutation in the Triple Helical Region of the Alpha 1 (II) Chain of the COL2A1 Protein Causes Non-Lethal Spondyloepiphyseal Dysplasia Congenita

Almatrafi, Ahmad; Alfadhli, Fatima; Khan, Yasir Naseem; Afzal, Sibtain; Hashmi, Jamil Amjad; Ullah, Anhar; Albalawi, Alia M.; Basit, Sulman

doi:10.1089/gtmb.2018.0301

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…Variation in the phenotypic expression of different individuals suggests that some other genetic and environmental effects may play a role in the final clinical expression. [38][39][40] To date, the knowledge on the development of LCPD in humans is limited because of the vast number of mutations found in the COL2A1 gene and the variability in the clinical phenotype. [41,42] It is apparent that the process in which mutations in collagens alter connective tissues is complicated and cannot be described by one single pathway.…”

Section: Discussionmentioning

confidence: 99%

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

Yan

Wang²,

Zhang

2020

Preprint

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Background: The aim of this study was to identify genetic factors and chromosomal regions contributing to osteonecrosis of the femoral head (ONFH) in a Chinese family with presentations of Legg-Calvé-Perthes Disease (LCDP). Methods: In this study, we performed whole exon sequencing of a Chinese family with LCPD for mutation detection. Ten members had ONFH in twenty-seven family members in four generations family, 5 unaffected members of the studied family and 5 normal peoples as control were underwent whole exome sequencing for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. Results: In this Chinese family affected by LCPD, the mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain was present in 10 patients but absent in 5 unaffected members of the studied family and in 5 control chromosomes from unaffected individuals of matched geographical ancestry. The COL2A1 gene mutation was further validated by Sanger sequencing, confirmed that were heterozygous for the mutation. Then, we identified the p.Gly1170Ser mutation in exon 50 of COL2A1 in a Chinese family with LCPD. Conclusions: This study maps the mutation of mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain in a Chinese family of LCPD, which causes osteonecrosis of femoral head.

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Section: Discussionmentioning

confidence: 99%

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

Yan

Wang²,

Zhang

2020

Preprint

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“…1a ), exome sequencing was performed at the Cologne Center for Genomics (CCG, Cologne, Germany). Details of the sequencing protocol are provided elsewhere ( 17 , 18 ). Briefly, 1 μg fragmented DNA was sonicated, and the fragments were subjected to end-repair and adaptor-ligation, including incorporation of sample index barcodes.…”

Section: Methodsmentioning

confidence: 99%

Apparent Missense Variant in COL7A1 Causes a Severe Form of Recessive Dystrophic Epidermolysis Bullosa via Effects on Splicing

Uddin¹,

Cesarato²,

Humbatova³

et al. 2020

Acta Derm Venereol

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Dystrophic epidermolysis bullosa is an inherited skin disorder characterized by fragile skin that is prone to blistering. We report here a consanguineous Pakistani family with two siblings, in whom a severe recessive dystrophic epidermolysis bullosa was suspected. Using whole-exome sequencing for one sibling, the homozygous base substitution c.7249C>G in COL7A1 was identified, and could be confirmed in the other sibling by Sanger sequencing. In our exome data, this mutation was annotated as a missense substitution (p.Gln2417Glu), but in silico tools indicated a possible effect on splicing. Using the ExonTrap vector it was verified that the mutation leads to activation of a cryptic donor splice site, which leads to loss of 26 nucleotides, and a frameshift event predicted to result in a truncated protein (p.Q2417Sfs*57). The present report describes an apparent COL7A1 missense substitution with an unexpected consequence on splicing that leads to a severe recessive dystrophic epidermolysis bullosa phenotype.

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“…Approximately 200 ng genomic DNA of two affected and two unaffected members were taken for genotyping as per protocol described elsewhere. 26,27 Illumina genome studio and homozygosity mapper 28,29 were employed to detect common regions sharing homozygosity amongst the affected members.…”

Section: Whole Genome Single Nucleotide Polymorphism (Snp) Genotypingmentioning

confidence: 99%

Further Evidence of a Recessive Variant in COL1A1 as an Underlying Cause of Ehlers–Danlos Syndrome: A Report of a Saudi Founder Mutation

Almatrafi

Hashmi

Fadhli

et al. 2020

Global Medical Genetics

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Ehlers–Danlos syndrome (EDS) is a group of clinically and genetically heterogeneous disorder of soft connective tissues. The hallmark clinical features of the EDS are hyperextensible skin, hypermobile joints, and fragile vessels. It exhibits associated symptoms including contractures of muscles, kyphoscoliosis, spondylodysplasia, dermatosparaxis, periodontitis, and arthrochalasia. The aim of this study is to determine the exact subtype of EDS by molecular genetic testing in a family segregating EDS in an autosomal recessive manner. Herein, we describe a family with two individuals afflicted with EDS. Whole exome sequencing identified a homozygous missense mutation (c.2050G > A; p.Glu684Lys) in the COL1A1 gene in both affected individuals, although heterozygous variants in the COL1A1 are known to cause EDS. Recently, only one report showed homozygous variant as an underlying cause of the EDS in two Saudi families. This is the second report of a homozygous variant in the COL1A1 gene in a family of Saudi origin. Heterozygous carriers of COL1A1 variant are asymptomatic. Interestingly, the homozygous variant identified previously and the one identified in this study are same (c.2050G > A). The identification of a unique homozygous mutation (c.2050G > A) in three Saudi families argues in favor of a founder effect.

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A Heterozygous Mutation in the Triple Helical Region of the Alpha 1 (II) Chain of the COL2A1 Protein Causes Non-Lethal Spondyloepiphyseal Dysplasia Congenita

Cited by 6 publications

References 28 publications

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

Mutation of COL2A1 in a Chinese Family with Presentations of Legg-Calvé-Perthes Disease

Apparent Missense Variant in COL7A1 Causes a Severe Form of Recessive Dystrophic Epidermolysis Bullosa via Effects on Splicing

Further Evidence of a Recessive Variant in COL1A1 as an Underlying Cause of Ehlers–Danlos Syndrome: A Report of a Saudi Founder Mutation

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