title: Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3.
abstract: As part of a large-scale, systematic effort to unravel the molecular causes of autosomal recessive mental retardation, we have previously described a novel syndrome consisting of mental retardation, coloboma, cataract and kyphosis (Kahrizi syndrome, OMIM 612713) and mapped the underlying gene to a 10.4-Mb interval near the centromere on chromosome 4. By combining array-based exon enrichment and next generation sequencing, we have now identified a homozygous frameshift mutation (c.203dupC; p.Phe69LeufsX2) in the gene for steroid 5α-reductase type 3 (SRD5A3) as the disease-causing change in this interval. Recent evidence indicates that this enzyme is required for the conversion of polyprenol to dolichol, a step that is essential for N-linked protein glycosylation. Independently, another group has recently observed SRD5A3 mutations in several families with a type 1 congenital disorder of glycosylation (CDG type Ix, OMIM 212067), mental retardation, cerebellar ataxia and eye disorders. Our results show that Kahrizi syndrome and this CDG Ix subtype are allelic disorders, and they illustrate the potential of next-generation sequencing strategies for the elucidation of single gene defects.
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Cougar Hao
authors.initials: CH
authors.lastname: Hu
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Seyedeh Sedigheh
authors.initials: SS
authors.lastname: Abedini
authors.forename: Shirin
authors.initials: S
authors.lastname: Ghadami
authors.forename: Roxana
authors.initials: R
authors.lastname: Kariminejad
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: H-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D002386:Cataract / Q000151:congenital / Q000235:genetics; D002524:Cerebellar Ataxia / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003103:Coloboma / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons / Q000235:genetics; D005128:Eye Diseases / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007738:Kyphosis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548469:SRD5A3 protein, human