Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome
| Autor: | F. Lucy Raymond, Jacques L. Michaud, Gail E. Herman, Jozef Gecz, Marco A. Marra, Barbara McGillivray, David W. Stockton, Jane Hurlburt, Robert D. Steiner, Richard A. Moore, Richard I. Kelley, Michelle Demos, Andrea E. DeBarber, Christèle du Souich, Laura Arbour, Keith W. McLarren, Ryan D. Morin, Paula J. Waters, Tesa M. Severson, Jessica E. Paul, Diane Wu, Yongjun Zhao, Patrick S. Tarpey, Michael R. Stratton, David Cunningham, Steven J.M. Jones, Louise S. Merkens, Karl-Heinz Grzeschik, Debbie Shears, Charles E. Schwartz, Lisa E. Kratz, Athena Chou, Jianghong An, Guy A. Rouleau, Margot I. Van Allen, Jingyi Yin, Cornelius F. Boerkoel, Glenda Hendson, Raffaella Smith, Tanya N. Nelson |
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| Jazyk: | angličtina |
| Předmět: |
Adult
Male 3-Hydroxysteroid Dehydrogenases Adolescent Molecular Sequence Data Biology Young Adult Exon chemistry.chemical_compound Report Genetics medicine Animals Humans Abnormalities Multiple Genetics(clinical) Amino Acid Sequence Allele Alleles Genetics (clinical) X chromosome Sequence Homology Amino Acid Cholesterol Temperature Genetic Diseases X-Linked Exons CHILD syndrome medicine.disease Molecular biology Sterol Pedigree Xq28 Complementation chemistry Mutation Female lipids (amino acids peptides and proteins) |
| Zdroj: | The American Journal of Human Genetics. (6):905-914 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2010.11.004 |
| Popis: | CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development. |
| Databáze: | OpenAIRE |
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