A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Cooper, Michael K.; Wassif, Christopher A.; Krakowiak, Patrycja A.; Taipale, Jussi; Gong, Ruoyu; Kelley, Richard I.; Porter, Forbes D.; Beachy, Philip A.

doi:10.1038/ng1134

Cited by 366 publications

(341 citation statements)

References 31 publications

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“…7 Disruption of SHH signaling has been implicated in syndromes of deficient cholesterol biosynthesis, such as Smith-Lemli-Optiz syndrome (SLOS). [282][283][284] Interestingly, SLOS is a neurodevelopmental disorder characterized by high rates of autism. 285,286 The disease is caused by mutations in DHCR7, leading to a disruption in cholesterol synthesis and an accumulation of precursor sterols.…”

Section: Genes Responsive To Environmental Factorsmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Section: Genes Responsive To Environmental Factorsmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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“…Analyses of DHCR7 mutant animal models (Cooper et al, 2003;Yu et al, 2004) have provided considerable information about the molecular and phenotypic consequences of a total loss of DHCR7 function. In order to analyze the loss-of-function of Xdhcr7 in a non-placental vertebrate, we knocked down the synthesis of the endogenous XDHCR7 protein by means of an antisense morpholino oligonucleotide (Xdhcr7-morpholino).…”

Section: Loss Of Xdhcr7 Function Impairs the Early Formation Of Neuramentioning

confidence: 99%

“…Since cholesterol homeostasis is important for the proper range of Hh signalling, the regulation of Xdhcr7 expression by Hh could be part of the mechanism by which the Hh protein controls its own range of signalling. Moreover, defective response to hedgehog signalling has been reported in disorders of cholesterol biosynthesis (Cooper et al, 2003); therefore, down-regulation of Xdhcr7 expression by Hh-signalling may define a new mechanism in which Hh gradually renders receiving cells less responsive to its signal at least along the neural tube.…”

Section: The Expression Of Xdhcr7 Is Spatially Restricted and Overlamentioning

confidence: 99%

“…Accumulating data provides evidence for a pivotal role played by cholesterol in development and pattern formation, mainly through its involvement in the maturation and transduction of the Hedgehog signal (Porter et al, 1996;Kuwabara and Labouesse, 2002;McCarthy et al, 2002;McCarthy and Argraves, 2003). Disorders of cholesterol biosynthesis are among the most severe human genetic diseases, since they are all characterised by dysmorphogenesis of multiple organs (Moebius et al, 2000;Kelley and Herman, 2001;Nwokoro et al, 2001;Cooper et al, 2003). The de novo cholesterol biosynthesis involves more than 30 enzyme-catalysed reactions, of which the NADPH-dependent reduction of hydroxymethyl glutaryl coenzyme A is rate limiting (Herman, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Until now, isolation of DHCR7 cDNA has been reported for several species including humans, mice Moebius et al, 1998), rats (Bae et al, 1999), and Arabidopsis (Lecain et al, 1996). Experimental trials have attempted to understand the molecular mechanism of the SLOS mutations, and deficient Hedgehog signaling has been suggested as a possible contributing phenomenon (Cooper et al, 2003;Yu et al, 2004). Here we report on the isolation and molecular characterization of Xenopus laevis dhcr7 (Xdhcr7) cDNA.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

Tadjuidje¹,

Hollemann²

2006

Developmental Dynamics

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7-dehydrocholesterol reductase (7-Dhcr) catalyses the final step in the pathway of cholesterol biosynthesis. Human patients with inborn errors of 7-Dhcr (Smith-Lemli-Opitz-Syndrome) have elevated serum levels of 7-dehydrocholesterol but low levels of cholesterol, which in phenotypical terms can result in growth retardation, craniofacial abnormalities including cleft palate, and reduced metal abilities. This study reports the isolation and molecular characterisation of 7-dehydrocholesterol reductase (Xdhcr7) from Xenopus laevis. During early embryonic development, the expression of Xdhcr7 is first of all spatially restricted to the Spemann's organizer and later to the notochord. In both tissues, Xdhcr7 is coexpressed with Sonic hedgehog (Shh), which itself is cholesterol-modified during autoproteolytic cleavage. Data from Xdhcr7 overexpression and knockdown experiments reveals that a tight control of cholesterol synthesis is particularly important for proper development of the central and peripheral nervous system.

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Statins for Smith-Lemli-Opitz syndrome

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Bianconi

Livinski

et al. 2020

Cochrane Database of Systematic Reviews

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have no known conflicts of interest to be disclosed. Simona Bianconi and Forbes D. Porter conducted and published the largest trial to date on statin therapy in SLOS patients: "A Placebo-Controlled Trial of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome" (Wassif 2017). As a result, they will be excluded from evaluating the eligibility of that study for inclusion in our review, as well as their exclusion from any subsequent data handling pertaining to that study.

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A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis

Cited by 366 publications

References 31 publications

Advances in behavioral genetics: mouse models of autism

Advances in behavioral genetics: mouse models of autism

Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

Statins for Smith-Lemli-Opitz syndrome

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