Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome

Keith W. McLarren, Tesa M. Severson, Christle Du Souich, David W. Stockton, Lisa E. Kratz, David Cunningham, Glenda Hendson, Ryan D. Morin, Diane Wu, Jessica E. Paul, Jianghong An, Tanya N. Nelson, Athena Chou, Andrea E. Debarber, Louise S. Merkens, Jacques L. Michaud, Paula J. Waters, Jingyi Yin, Barbara McGillivray, Michelle DemosGuy A. Rouleau, Karl Heinz Grzeschik, Raffaella Smith, Patrick S. Tarpey, Debbie Shears, Charles E. Schwartz, Jozef Gecz, Michael R. Stratton, Laura Arbour, Jane Hurlburt, Margot I. Van Allen, Gail E. Herman, Yongjun Zhao, Richard Moore, Richard Ian Kelley, Steven J.M. Jones, Robert D. Steiner, F. Lucy Raymond, Marco A. Marra, Cornelius F. Boerkoel

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)905-914
Number of pages10
JournalAmerican journal of human genetics
Issue number6
StatePublished - Dec 10 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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