Genotypic and phenotypic analysis of 396 individuals with mutations in<i>Sonic Hedgehog</i>

Solomon, Benjamin D.; Bear, Kelly A.; Wyllie, Adrian; Keaton, Amelia A.; Dubourg, Christèle; David, Véronique; Mercier, Sandra; Odent, Sylvie; Hehr, Ute; Paulussen, Aimée D C; Clegg, Nancy J.; Delgado, Mauricio R.; Bale, Sherri J.; Lacbawan, Felicitas; Ardinger, Holly H; Aylsworth, Arthur S.; Bhengu, Ntombenhle Louisa; Braddock, Stephen R.; Brookhyser, Karen; Burton, Barbara K.; Gaspar, Harald; Grix, Art; Horovitz, Dafne Dain Gandelman; Kanetzke, Erin; Kayserili, Hülya; Lev, Dorit; Nikkel, Sarah M.; Norton, Mary E.; Roberts, Richard M.; Saal, Howard M.; Schaefer, Gerald; Schneider, Adele; Smith, Erika K.; Sowry, Ellen; Spence, M. Anne; Shalev, Stavit A.; Steiner, Carlos Eduardo; Thompson, Elizabeth; Winder, Thomas; Balog, Joan Z.; Hadley, Donald W.; Zhou, Nan; Pineda-Álvarez, Daniel E.; Roessler, Erich; Muenke, Maximilian

doi:10.1136/jmedgenet-2012-101008

Cited by 68 publications

(84 citation statements)

References 27 publications

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“…Shh null mice exhibit profound developmental defects [23], including holoprosencephaly (HPE), a condition defined by incomplete division of the forebrain, characterized by medial forebrain deficiency, and which commonly occurs with CL/P in clinical populations [23], [24]. In humans, mutations in SHH are the most commonly identified cause of non-chromosomal HPE, accounting for approximately 12% of such cases [25], [26]. However, in a recent analysis only 36% of SHH mutation carriers were found to have true HPE, with the remaining carriers classified as unaffected or as having microform HPE ( i.e.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate

et al. 2014

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Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient in utero exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly—a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.

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Section: Introductionmentioning

confidence: 99%

Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate

et al. 2014

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“…SHH mutations are most often associated with a microform or mild HPE, in contrast to mutations in other common HPE-related genes [Mercier et al, 2011;Solomon et al, 2012]. In the same way, it seems that a HPE phenotype associated with cytogenetic rearrangements occurring in the upstream portion of SHH gene is more often mild with predominantly HPE microforms ( table 1 ).…”

Section: Discussionmentioning

confidence: 96%

“…SHH is the most frequently mutated gene in HPE accounting for approximately 12% of cases [Roessler et al, 2009]. Despite of no clear phenotype-genotype correlation, the mutations of this gene are more related to milder forms of HPE such as microforms than those in other common HPE-related genes [Mercier et al, 2011;Solomon et al, 2012].The Currarino triad associates partial sacral agenesis with presacral mass and anorectal malformations. Mutations in the gene MNX1 (HLXB9) (MIM 142994), located in 7q36.3, were identified in nearly all patients with a familial form of Currarino syndrome and in 30% of those with a sporadic form [Lynch et al, 2000].…”

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confidence: 99%

Currarino Syndrome and HPE Microform Associated with a 2.7-Mb Deletion in 7q36.3 Excluding SHH Gene

Coutton

Poreau²,

Devillard

et al. 2013

Mol Syndromol

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Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon and can be caused by environmental and genetic factors. HPE is usually described as a continuum of brain malformations from the most severe alobar HPE to the middle interhemispheric fusion variant or syntelencephaly. A microform of HPE is limited to craniofacial features such as congenital nasal pyriform aperture stenosis and single central maxillary incisor, without brain malformation. Among the heterogeneous causes of HPE, point mutations and deletions in the SHH gene at 7q36 have been identified as well as extremely rare chromosomal rearrangements in the long-range enhancers of this gene. Here, we report a boy with an HPE microform associated with a Currarino syndrome. Array CGH detected a de novo 2.7-Mb deletion in the 7q36.3 region including the MNX1 gene, usually responsible for the Currarino triad but excluding SHH, which is just outside the deletion. This new case provides further evidence of the importance of the SHH long-range enhancers in the HPE spectrum.

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“…Each individual was tested for mutations in the four most common genes involved in nonchromosomal, nonsyndromic holoprosencephaly (HPE) ( SHH , ZIC2 , SIX3 , and TGIF1 ) using previously described methods [13]. In addition to the standard evaluation described elsewhere [14], a subset of patients was examined at the NIH Clinical Center (NIH-CC) under NHGRI protocol 04-HG-00923 (clinicaltrials.gov: NCT00088426). Clinical testing included an abdominal ultrasound, fasting lipid profiles, and hepatic function tests.…”

Section: Methodsmentioning

confidence: 99%

Human germline hedgehog pathway mutations predispose to fatty liver

Guillen-Sacoto

Martinez

Abe

et al. 2017

Journal of Hepatology

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Background & Aims Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations affecting this pathway. Methods Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/−) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Results Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/− mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/− mice exposed to high-fat diet. Conclusions Our results indicate that germline mutations disrupting Hh signaling promote liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway.

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Genotypic and phenotypic analysis of 396 individuals with mutations inSonic Hedgehog

Abstract: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

Cited by 68 publications

References 27 publications

Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate

Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate

Currarino Syndrome and HPE Microform Associated with a 2.7-Mb Deletion in 7q36.3 Excluding SHH Gene

Human germline hedgehog pathway mutations predispose to fatty liver

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