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.
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References
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Acknowledgements
We are grateful to the patients and the parents of the family for their cooperation. We thank Vera Kalscheuer and Stefan Haas for bioinformatic support, and Ines Müller, Corinna Menzel and Melanie Bienek for technical assistance. This work was supported by the Iranian National Science Foundation (to HN), the Max Planck Innovation Funds, and the German Federal Ministry of Education and Research through the NGFNplus – MRNET (to HHR).
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Kahrizi, K., Hu, C., Garshasbi, M. et al. Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3. Eur J Hum Genet 19, 115–117 (2011). https://doi.org/10.1038/ejhg.2010.132
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DOI: https://doi.org/10.1038/ejhg.2010.132
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