TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual

Unusual phenotype with progressive vertebral fusion in a girl with an apparently balanced t(10;20)(p11;p13) translocation

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Génétique moléculaire de la maladie de Hirschsprung : un modèle de neurocristopathie multigénique

La maladie de Hirschsprung (MH, mégacôlon aganglionique) est une malformation congénitale fréquente considérée comme une neurocristopathie d’origine multigénique. Plusieurs gènes de susceptibilité ont été identifiés dans cette pathologie dont le proto-oncogène RET, le récepteur B aux endothélines (EDNRB), et l’un de ses ligands l’endothéline 3 (EDN3). RET est le gène majeur et une mutation est identifiée dans 50 % des cas familiaux et 15 à 20 % des cas isolés de MH. Les gènes de la cascade des endothélines, identifiés grâce aux modèles murins spontanés associant un mégacôlon et une anomalie de pigmentation du pelage, rendent compte à l’état homozygote d’une association rare, le syndrome de Shah-Waardenburg et, à l’état hétérozygote, d’environ 5 % des cas de MH isolés. Ces résultats démontrent l’hétérogénéité génétique de la MH. D’autres gènes candidats, comme en particulier les ligands de RET (GDNF et Neurturine) ne sont à eux seuls ni nécessaires, ni suffisants pour rendre compte de la maladie. La MH paraît un excellent modèle pour l’étude des maladies d’origine multigénique et pourra être d’une aide précieuse dans l'approche de maladies multigéniques fréquentes et plus complexes, comme le diabète ou l’hypertension artérielle. Enfin, la connaissance des bases moléculaires dans cette pathologie devrait enrichir nos connaissances sur le développement du système nerveux entérique chez l’Homme

Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation

A 4-base pair deletion in the neuronal serine protease neurotrypsin gene was associated with autosomal recessive nonsyndromic mental retardation (MR). In situ hybridization experiments on human fetal brains showed that neurotrypsin was highly expressed in brain structures involved in learning and memory. Immuno-electron microscopy on adult human brain sections revealed that neurotrypsin is located in presynaptic nerve endings, particularly over the presynaptic membrane lining the synaptic cleft. These findings suggest that neurotrypsin-mediated proteolysis is required for normal synaptic function and suggest potential insights into the pathophysiological bases of mental retardation

Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.

Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system