Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome

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dc.contributor.authorGecz, J.
dc.date.issued2010
dc.description.abstractCK 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.
dc.description.statementofresponsibilityKeith W. McLarren... Jozef Gecz... et al.
dc.identifier.citationAmerican Journal of Human Genetics, 2010; 87(6):905-914
dc.identifier.doi10.1016/j.ajhg.2010.11.004
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/62960
dc.language.isoen
dc.publisherUniv Chicago Press
dc.rights© 2010 by The American Society of Human Genetics. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.ajhg.2010.11.004
dc.subjectAnimals
dc.subjectHumans
dc.subjectAbnormalities, Multiple
dc.subjectGenetic Diseases, X-Linked
dc.subject3-Hydroxysteroid Dehydrogenases
dc.subjectPedigree
dc.subjectTemperature
dc.subjectAmino Acid Sequence
dc.subjectSequence Homology, Amino Acid
dc.subjectMutation
dc.subjectAlleles
dc.subjectExons
dc.subjectMolecular Sequence Data
dc.subjectAdolescent
dc.subjectAdult
dc.subjectFemale
dc.subjectMale
dc.subjectYoung Adult
dc.titleHypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome
dc.typeJournal article
pubs.publication-statusPublished

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