Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome

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.

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

“…Skeletal involvement is mild; boys present with a thin body habitus with asthenic build, hyperextensible joints, scoliosis, kyphosis or lordosis, long limbs, and long fingers and toes, and they show no features of CHILD syndrome [48][49][50].…”

“…This condition is inherited in an X-linked recessive manner. Its clinical phenotype is characterised by intellectual disability, dysmorphic features, behavioural abnormalities and neural migration anomalies (pachygyria, polymicrogyria) [48].…”

Expression profile of NSDHL in human peripheral tissues

“…Understanding the relationship between NSDHL expression and disease requires extension of expression studies in mouse (Cunningham et al 2009;Laubner et al 2003;Liu et al 1999;Caldas et al 2005) to the human. Furthermore, while human NSDHL expression has been profiled previously within the CNS (McLarren et al 2010), human NSDHL expression in peripheral tissues has not been profiled. Herein therefore we profile human NSDHL protein expression and mouse Nsdhl mRNA expression outside of the CNS.…”

“…The protein localizes to the surface of the endoplasmic reticulum and lipid droplets (Caldas and Herman 2003). The divergent clinical phenotypes of CHILD syndrome and CK syndrome can be explained in part by the different alleles of NSDHL; patients with CHILD syndrome have null alleles resulting in complete loss of functional NSDHL Kim et al 2005;Danarti et al 2010), while patients with CK syndrome have hypomorphic temperature-sensitive alleles (McLarren et al 2010). However, the mechanism by which NSDHL deficiency causes dysmorphism remains unclear.…”

“…CHILD and CK syndromes are caused by deficiency of NSDHL (Konig et al 2000;Bornholdt et al 2005;McLarren et al 2010). NSDHL is a sterol dehydrogenase that is a member of a complex that removes C-4 methyl groups in one of the later steps of the cholesterol biosynthesis pathway (Liu et al 1999).…”