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

研究成果: Article

174 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)478-484
ページ数7
ジャーナルAmerican Journal of Medical Genetics
66
発行部数4
DOI
出版物ステータスPublished - 1996
外部発表Yes

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

ASJC Scopus subject areas

  • Genetics(clinical)

これを引用

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.

:: American Journal of Medical Genetics, 巻 66, 番号 4, 1996, p. 478-484.

研究成果: Article

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?. :: American Journal of Medical Genetics. 1996 ; 巻 66, 番号 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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AU - Kosaki, Kenjiro

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AU - Palumbos, J. C.

AU - Muenke, M.

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N2 - 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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