Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome

Keith W. McLarren, Tesa M. Severson, Christle Du Souich, David W. Stockton, Lisa 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 I. Kelley, Steven J M Jones, Robert D. Steiner, F. Lucy Raymond, Marco A. Marra, Cornelius F. Boerkoel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)905-914
Number of pages10
JournalAmerican Journal of Human Genetics
Volume87
Issue number6
DOIs
StatePublished - Dec 10 2010

Fingerprint

Alleles
Cholesterol
Temperature
Sterols
Intellectual Disability
Cerebrospinal Fluid
Mutation
Protein Stability
Protein Folding
X Chromosome
Human Development
NAD
Exons
Oxidoreductases
Nucleotides
Yeasts
Steroids
Brain
Enzymes
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

McLarren, K. W., Severson, T. M., Du Souich, C., Stockton, D. W., Kratz, L., Cunningham, D., ... Boerkoel, C. F. (2010). Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. American Journal of Human Genetics, 87(6), 905-914. https://doi.org/10.1016/j.ajhg.2010.11.004

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

In: American Journal of Human Genetics, Vol. 87, No. 6, 10.12.2010, p. 905-914.

Research output: Contribution to journalArticle

McLarren, KW, Severson, TM, Du Souich, C, Stockton, DW, Kratz, L, 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, SJM, Steiner, RD, Raymond, FL, Marra, MA & Boerkoel, CF 2010, 'Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome', American Journal of Human Genetics, vol. 87, no. 6, pp. 905-914. https://doi.org/10.1016/j.ajhg.2010.11.004
McLarren KW, Severson TM, Du Souich C, Stockton DW, Kratz L, Cunningham D et al. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. American Journal of Human Genetics. 2010 Dec 10;87(6):905-914. https://doi.org/10.1016/j.ajhg.2010.11.004
McLarren, Keith W. ; Severson, Tesa M. ; Du Souich, Christle ; Stockton, David W. ; Kratz, Lisa ; Cunningham, David ; Hendson, Glenda ; Morin, Ryan D. ; Wu, Diane ; Paul, Jessica E. ; An, Jianghong ; Nelson, Tanya N. ; Chou, Athena ; Debarber, Andrea E. ; Merkens, Louise S. ; Michaud, Jacques L. ; Waters, Paula J. ; Yin, Jingyi ; McGillivray, Barbara ; Demos, Michelle ; Rouleau, Guy A. ; Grzeschik, Karl Heinz ; Smith, Raffaella ; Tarpey, Patrick S. ; Shears, Debbie ; Schwartz, Charles E. ; Gecz, Jozef ; Stratton, Michael R. ; Arbour, Laura ; Hurlburt, Jane ; Van Allen, Margot I. ; Herman, Gail E. ; Zhao, Yongjun ; Moore, Richard ; Kelley, Richard I. ; Jones, Steven J M ; Steiner, Robert D. ; Raymond, F. Lucy ; Marra, Marco A. ; Boerkoel, Cornelius F. / Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. In: American Journal of Human Genetics. 2010 ; Vol. 87, No. 6. pp. 905-914.
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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.",
author = "McLarren, {Keith W.} and Severson, {Tesa M.} and {Du Souich}, Christle and Stockton, {David W.} and Lisa Kratz and David Cunningham and Glenda Hendson and Morin, {Ryan D.} and Diane Wu and Paul, {Jessica E.} and Jianghong An and Nelson, {Tanya N.} and Athena Chou and Debarber, {Andrea E.} and Merkens, {Louise S.} and Michaud, {Jacques L.} and Waters, {Paula J.} and Jingyi Yin and Barbara McGillivray and Michelle Demos and Rouleau, {Guy A.} and Grzeschik, {Karl Heinz} and Raffaella Smith and Tarpey, {Patrick S.} and Debbie Shears and Schwartz, {Charles E.} and Jozef Gecz and Stratton, {Michael R.} and Laura Arbour and Jane Hurlburt and {Van Allen}, {Margot I.} and Herman, {Gail E.} and Yongjun Zhao and Richard Moore and Kelley, {Richard I.} and Jones, {Steven J M} and Steiner, {Robert D.} and Raymond, {F. Lucy} and Marra, {Marco A.} and Boerkoel, {Cornelius F.}",
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T1 - Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome

AU - McLarren, Keith W.

AU - Severson, Tesa M.

AU - Du Souich, Christle

AU - Stockton, David W.

AU - Kratz, Lisa

AU - Cunningham, David

AU - Hendson, Glenda

AU - Morin, Ryan D.

AU - Wu, Diane

AU - Paul, Jessica E.

AU - An, Jianghong

AU - Nelson, Tanya N.

AU - Chou, Athena

AU - Debarber, Andrea E.

AU - Merkens, Louise S.

AU - Michaud, Jacques L.

AU - Waters, Paula J.

AU - Yin, Jingyi

AU - McGillivray, Barbara

AU - Demos, Michelle

AU - Rouleau, Guy A.

AU - Grzeschik, Karl Heinz

AU - Smith, Raffaella

AU - Tarpey, Patrick S.

AU - Shears, Debbie

AU - Schwartz, Charles E.

AU - Gecz, Jozef

AU - Stratton, Michael R.

AU - Arbour, Laura

AU - Hurlburt, Jane

AU - Van Allen, Margot I.

AU - Herman, Gail E.

AU - Zhao, Yongjun

AU - Moore, Richard

AU - Kelley, Richard I.

AU - Jones, Steven J M

AU - Steiner, Robert D.

AU - Raymond, F. Lucy

AU - Marra, Marco A.

AU - Boerkoel, Cornelius F.

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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.

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