Mutations in the C-Terminal Domain of Sonic Hedgehog Cause Holoprosencephaly

Roessler, Erich; Belloni, Elena; Gaudenz, Karin; Vargas, Fernando; Scherer, Stephen W.; Tsui, Lap Chee; Muenke, Maximilian

doi:10.1093/hmg/6.11.1847

Cited by 169 publications

(151 citation statements)

References 39 publications

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“…Mutations in SHH have been found in some patients with microcephaly but without HPE. 17,18 Therefore, we suggest that the gain-of-function or duplication of PTCH1 may result in microcephaly with or without HPE. We propose that patients with microcephaly or HPE of unknown origin should be screened for PTCH1 duplication.…”

Section: Discussionmentioning

confidence: 90%

PTCH1 duplication in a family with microcephaly and mild developmental delay

et al. 2008

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With the exception of the X chromosome, genomic deletions appear to be more prevalent than duplications. Because of a lack of accurate diagnostic methods, submicroscopic duplications have been under-ascertained for a long period. The development of array CGH has enabled the detection of chromosomal microduplications with nearly the same sensitivity as deletions, leading to the discovery of previously unrecognized syndromes. Using a clinical targeted oligonucleotide array (CMA-V6.3 OLIGO), we identified an B360-kb duplication in 9q22.32 in a 21-month-old boy with developmental delay, failure to thrive, and microcephaly. The same duplication was identified in the patient's mother who is also microcephalic and mildly delayed. We have sequenced the chromosomal breakpoints and determined the duplication as tandem in orientation and 363 599 bp in size. The duplicated segment harbors the entire PTCH1 gene. Deletions or loss-of-function mutations of PTCH1 result in basal cell nevus syndrome (Gorlin syndrome), whereas gain-of-function mutations were proposed to lead to holoprosencephaly 7. We propose that patients with microcephaly or holoprosencephaly of unknown origin should also be screened for PTCH1 duplication.

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Section: Discussionmentioning

confidence: 90%

PTCH1 duplication in a family with microcephaly and mild developmental delay

et al. 2008

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“…The hedgehog signaling pathway is fundamental in early embryonic patterning, and Shh mutations are associated with holoprosencephaly in humans. 22 The cellular concentration of cholesterol is regulated by the control of its biosynthesis (de novo synthesis from acetyl CoA) and uptake of circulating low density lipoproteins (LDL) cholesterol. Reverse cholesterol transport (from peripheral cells to the liver) also occurs through high density lipoproteins (HDL).…”

Section: Cellular Roles Of Cholesterolmentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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Abstract-Retinoic acid receptor-related Orphan Receptor ␣ (ROR␣) is a member of the nuclear hormone receptor superfamily. ROR␣ has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of ROR␣. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR␣ activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, ROR␣ appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making ROR␣ an intracellular cholesterol target. Key Words: ROR␣ Ⅲ cholesterol Ⅲ statins Ⅲ atherosclerosis Ⅲ lipid homeostasis R etinoic acid receptor-related Orphan Receptor ␣ (ROR␣), initially described as an orphan nuclear receptor, has recently been deorphanized by the identification of its natural ligand as cholesterol or a cholesterol derivative. 1,2 ROR␣ has been shown to be implicated in the development and/or differentiation of many tissues, and provides protection against age-related degenerative processes, including atherosclerosis. In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target. 1

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“…Mutations in SHH are known to cause holoprosencephaly (HPE) in humans [15,16]. More recently, IHH was shown to be a disease locus for brachydactyly type A1 (BDA1) [17,18].…”

Section: Introductionmentioning

confidence: 99%

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Xiao

et al. 2011

Cell Res

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Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.

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Mutations in the C-Terminal Domain of Sonic Hedgehog Cause Holoprosencephaly

Cited by 169 publications

References 39 publications

PTCH1 duplication in a family with microcephaly and mild developmental delay

PTCH1 duplication in a family with microcephaly and mild developmental delay

The “CholesteROR” Protective Pathway in the Vascular System

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

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