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https://hdl.handle.net/2440/62960
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Type: | Journal article |
Title: | Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome |
Author: | Gecz, J. |
Citation: | American Journal of Human Genetics, 2010; 87(6):905-914 |
Publisher: | Univ Chicago Press |
Issue Date: | 2010 |
ISSN: | 0002-9297 1537-6605 |
Statement of Responsibility: | Keith W. McLarren... Jozef Gecz... et al. |
Abstract: | 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. |
Keywords: | Animals Humans Abnormalities, Multiple Genetic Diseases, X-Linked 3-Hydroxysteroid Dehydrogenases Pedigree Temperature Amino Acid Sequence Sequence Homology, Amino Acid Mutation Alleles Exons Molecular Sequence Data Adolescent Adult Female Male Young Adult |
Rights: | © 2010 by The American Society of Human Genetics. All rights reserved. |
DOI: | 10.1016/j.ajhg.2010.11.004 |
Published version: | http://dx.doi.org/10.1016/j.ajhg.2010.11.004 |
Appears in Collections: | Aurora harvest 5 Paediatrics publications |
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