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Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

ABSTRACT: Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS.We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis.We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults.These data suggest that the c.1167insA FKTN mutation described by us is a founder mutation that can be used to target diagnostic testing and carrier screening in the Ashkenazi Jewish population.

SUBMITTER: Chang W

PROVIDER: S-EPMC2735827 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

Chang Wendy W Winder Thomas L TL LeDuc Charles A CA Simpson Lynn L LL Millar William S WS Dungan Jeffrey J Ginsberg Norman N Plaga Stacey S Moore Steven A SA Chung Wendy K WK

Prenatal diagnosis 20090601 6

<h4>Objective</h4>Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify th ...[more]

PMID: 19266496

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Project description:Cerebral cavernous malformations can occur sporadically or are caused by mutations in one of three identified genes. Cerebral cavernous malformations often remain clinically silent until a mutation carrier suffers a stroke or seizure. Presymptomatic genetic testing has been valuable to follow and manage cerebral cavernous malformation mutation carriers. During routine diagnostic testing, we identified a two base pair change in seven unrelated people of Ashkenazi Jewish heritage. Because of the location of the variant beyond the invariant splice donor sequence, the change was reported as a variant of unknown significance. In this study, we determined whether this change was a disease-causing mutation and whether it represents a founder mutation in the Ashkenazi Jewish population.Transcripts arising from the normal and mutant alleles were examined by reverse transcription-polymerase chain reaction from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization.The two base pair change in CCM2, c.30 + 5_6delinsTT, segregated with affected status in the study families. Reverse transcription-polymerase chain reaction revealed loss of the transcript allele that was in phase with the mutation. The two base pair change, when tested in an in vitro synthetic splicing system, altered splice donor site utilization. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common single-nucleotide polymorphism haplotype in affected individuals.The two base pair change in CCM2, c.30 + 5_6delinsTT, disrupted proper splice donor utilization leading to a degraded transcript. Single nucleotide polymorphism haplotype analysis demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. These data have the potential to simplify genetic testing for cerebral cavernous malformation in the Ashkenazi Jewish population.

Dataset Information

Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

Publications

Founder Fukutin mutation causes Walker-Warburg syndrome in four Ashkenazi Jewish families.

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