Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?

R. I. Kelley, E. Roessler, R. C M Hennekam, G. L. Feldman, Kenjiro Kosaki, M. C. Jones, J. C. Palumbos, M. Muenke

Research output: Contribution to journalArticle

174 Citations (Scopus)

Abstract

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7- dehydrocholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3β-hydroxy-steroid-Δ7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol- modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.

Original languageEnglish
Pages (from-to)478-484
Number of pages7
JournalAmerican Journal of Medical Genetics
Volume66
Issue number4
DOIs
Publication statusPublished - 1996
Externally publishedYes

Fingerprint

Smith-Lemli-Opitz Syndrome
Holoprosencephaly
Hedgehogs
Cholesterol
Hedgehog Proteins
Sterols
Oxidoreductases
Steroids
Mutation

Keywords

  • cholesterol
  • holoprosencephaly
  • RSH/Smith-Lemli-Opitz syndrome
  • sonic hedgehog

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome : Does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? / Kelley, R. I.; Roessler, E.; Hennekam, R. C M; Feldman, G. L.; Kosaki, Kenjiro; Jones, M. C.; Palumbos, J. C.; Muenke, M.

In: American Journal of Medical Genetics, Vol. 66, No. 4, 1996, p. 478-484.

Research output: Contribution to journalArticle

Kelley, R. I. ; Roessler, E. ; Hennekam, R. C M ; Feldman, G. L. ; Kosaki, Kenjiro ; Jones, M. C. ; Palumbos, J. C. ; Muenke, M. / Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome : Does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?. In: American Journal of Medical Genetics. 1996 ; Vol. 66, No. 4. pp. 478-484.
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abstract = "The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7- dehydrocholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3β-hydroxy-steroid-Δ7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol- modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.",
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