Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.

Mark McIntosh,'s picture
PubMed URL: 
Boerkoel CF
Author List: 
McLarren KW
Severson TM
du Souich C
Stockton DW
Kratz LE
Cunningham D
Hendson G
Morin RD
Wu D
Paul JE
An J
Nelson TN
Chou A
DeBarber AE
Merkens LS
Michaud JL
Waters PJ
Yin J
McGillivray B
Demos M
Rouleau GA
Grzeschik KH
Smith R
Tarpey PS
Shears D
Schwartz CE
Gecz J
Stratton MR
Arbour L
Hurlburt J
Van Allen MI
Herman GE
Zhao Y
Moore R
Kelley RI
Jones SJ
Steiner RD
Raymond FL
Marra MA
Boerkoel CF
Am J Hum Genet
PubMed ID: 
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.
Published Date: 
December, 2010

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