Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.
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.
Department of Medical Genetics, Vancouver, Canada.
Keith W
KW
McLarren
Tesa M
TM
Severson
Christèle
C
du Souich
David W
DW
Stockton
Lisa E
LE
Kratz
David
D
Cunningham
Glenda
G
Hendson
Ryan D
RD
Morin
Diane
D
Wu
Jessica E
JE
Paul
Jianghong
J
An
Tanya N
TN
Nelson
Athena
A
Chou
Andrea E
AE
DeBarber
Louise S
LS
Merkens
Jacques L
JL
Michaud
Paula J
PJ
Waters
Jingyi
J
Yin
Barbara
B
McGillivray
Michelle
M
Demos
Guy A
GA
Rouleau
Karl-Heinz
KH
Grzeschik
Raffaella
R
Smith
Patrick S
PS
Tarpey
Debbie
D
Shears
Charles E
CE
Schwartz
Jozef
J
Gecz
Michael R
MR
Stratton
Laura
L
Arbour
Jane
J
Hurlburt
Margot I
MI
Van Allen
Gail E
GE
Herman
Yongjun
Y
Zhao
Richard
R
Moore
Richard I
RI
Kelley
Steven J M
SJ
Jones
Robert D
RD
Steiner
F Lucy
FL
Raymond
Marco A
MA
Marra
Cornelius F
CF
Boerkoel
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D005091:Exons; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D055815:Young Adult
D015096:3-Hydroxysteroid Dehydrogenases; C478776:Nsdhl protein, human