Gene/Protein Disease Symptom Drug Enzyme Compound
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Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
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PMID:[From monogenic to polygenic: model of Hirschsprung disease]. 988 24

Hirschsprung's disease, affecting one in 5000 live newborns, is the most common cause of neonatal intestinal obstruction. The obstruction or, later in life, constipation arises from the lack of enteric ganglia in the hindgut, thus resulting in poor coordination of peristalsis. Mutations in Hirschsprung patients have so far been reported in five genes associated in two different receptor-ligand systems, RET-GDNF/NTN and EDNRB-EDN-3, and an additional gene with yet unknown precise function, SOX10. We report the results of single-stranded conformation polymorphism screening of the endothelin-3 gene in a Swedish population-based material of 66 sporadic and nine familial Hirschsprung's disease cases. We have found a novel heterozygous mutation in exon 2, c.262insG, in a patient with sporadic short segment Hirschsprung's disease without any Waardenburg features. This frameshift results in a premature stop two codons further on. Because this stop is introduced 5' of the biologically active protein, this mutation can hence be predicted to result in haplo-insufficiency.
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PMID:A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung's disease. 1023 70

On some occasions, mutations of a gene cause different syndromes that may have similar phenotypes. For example, mutations of the MITF gene cause Waardenburg syndrome type 2 (Tassabehji et al, 1994; Nobukuni et al, 1996) as well as Tietz syndrome (Smith et al, 1997). On other occasions, mutations of different genes cause an identical syndrome. Molecular analyses of these genes may provide a good opportunity to not only understand such syndromes themselves but also the biologic aspects of cells relevant to these syndromes. By analyzing the genes for Waardenburg syndrome, we showed that PAX3, the gene responsible for Waardenburg syndrome type 1, regulates MITF, the gene responsible for Waardenburg syndrome type 2. Such epistatic relationships have been shown between other genes related to Waardenburg syndrome, and likely to construct a cascade. This paper proposes such a cascade, one that involves genes for PAX3, MITF, human MyoD, MYF5, c-MET, c-KIT, tyrosinase, TRP-1, human QNR-71, SOX10, EDNRB, and EDN3.
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PMID:A cascade of genes related to Waardenburg syndrome. 1053 86

Hirschsprung disease and Waardenburg syndrome are human genetic diseases characterized by distinct neural crest defects. Patients with Hirschsprung disease suffer from gastrointestinal motility disorders, whereas Waardenburg syndrome consists of defective melanocyte function, deafness, and craniofacial abnormalities. Mutations responsible for Hirschsprung disease and Waardenburg syndrome have been identified, and some patients have been described with characteristics of both disorders. Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation. Pax3 can bind to and activate expression of the c-RET gene, which is often mutated in Hirschsprung disease. Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome. Thus, Pax3, Sox10, and c-Ret are components of a neural crest development pathway, and interruption of this pathway at various stages results in neural crest-related human genetic syndromes.
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PMID:Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret. 1103 56

Piebaldism is an autosomal dominant disorder of melanocyte development characterized by white skin (leukoderma) and white hair (poliosis). In general, piebaldism has been distinguished from vitiligo by the presence of lesions from birth, the hyperpigmented macules of depigmented and normal skin, and the static course. We hypothesized that an 8-year-old girl and her mother who had unusual piebaldism of a progressive nature would have a novel mutation of the KIT gene, the gene that is altered in patients with piebaldism, or of the MITF (microphthalmia activating transcription factor) gene, which would be expected to cause type II Waardenburg syndrome, but is associated with a phenotype of progressive depigmentation in mice. Genomic DNA was extracted from the blood of affected and unaffected family members, and the KIT and MITF genes were sequenced. Genetic analysis of genomic DNA from both the mother and daughter with progressive piebaldism revealed a novel Val620Ala (1859T>C) mutation in the KIT gene, which was not detected in family members without progressive piebaldism or in 52 normal control individuals. This KIT mutation affects the intracellular tyrosine kinase domain and thus predicts a severe phenotype, as was the case in this family. Although other KIT mutations in the vicinity of codon 620 lead to the standard phenotype of static piebaldism, the Val620Ala mutation is novel and may result in a previously undescribed phenotype with melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of the hyperpigmented macules.
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PMID:A novel KIT mutation results in piebaldism with progressive depigmentation. 1117 89

Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB an EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
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PMID:[Molecular genetics of Hirschsprung disease: a model of multigenic neurocristopathy]. 1132 13

Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10. These phenotypic features suggest that SOX10 could regulate expression of other genes involved in the myelination process as well. Thus, we tested the ability of SOX10 to regulate expression of MBP, PMP22 and Connexin 32, three major proteins of the peripheral myelin. Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects fail to transactivate the Cx32 promoter. Moreover, we show that a mutation of the Cx32 promoter previously described in a patient with the X-linked form of Charcot-Marie-Tooth (CMTX) disease impairs SOX10 function. In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10.
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PMID:Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. 1173 43

The neurocristopathies encompass a spectrum of developmental disorders characterized by abnormalities of neural crest-derived structures. Neural crest cells are pluripotent progenitors and the mechanisms by which specific cell-fate decisions are regulated have emerged as an important field of study. Many neurocristopathies are characterized by defects in melanocyte differentiation that can result in pigmentation abnormalities and deafness. One example is Waardenburg syndrome that can be caused by mutations in the PAX3, SOX10 or MITF genes. Other neural crest-related disorders are associated with enteric ganglia defects, such as those caused by mutations in the SOX10 or c-RET genes. The Pax3 and Sox10 transcription factors can directly regulate both MITF and c-RET. Here, we show that Pax3 and Sox10 can physically interact and we map the interaction domains. We show that this interaction contributes to Pax3 and Sox10 synergistic activation of a conserved c-RET enhancer and it explains why Sox10 mutants that cannot bind to DNA retain the ability to activate this enhancer in the presence of Pax3. However, in the context of the MITF gene, Pax3 and Sox10 must each bind independently to DNA in order to achieve synergy. This difference is consistent with the different structures of the c-RET and MITF enhancers, and the different mechanisms by which Pax3 binds to these enhancers. These observations explain the phenotype in the mild form of Yemenite deaf-blind syndrome caused by specific SOX10 mutations in the HMG box that abrogate DNA binding without disrupting association with Pax3.
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PMID:Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer. 1266 17

SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis, overexpression of genes coding for structural myelin proteins such as P0 due to mutant SOX10 may explain the dysmyelination phenotype observed in the patients with an additional neurological disorder.
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PMID:Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation. 1452 91

We report two cases in which the probands presented with deafness and a family history of a dominantly inherited auditory pigmentary syndrome, yet the cause of deafness in each proband was not associated with the pigmentary abnormalities but was a result of mutations in SLC26A4, the gene mutated in Pendred's syndrome. The first case is a young woman with congenital sensorineural hearing loss and a family history of piebaldism. Despite showing no pigmentary abnormalities, the proband was found to harbor the same KIT mutation as her relatives affected by piebaldism, as well as two mutations in the SLC26A4 gene. In the second case, 2-year-old identical twin boys born to deaf parents presented with congenital sensorineural deafness and an extensive maternal family history of Waardenburg's syndrome type I (WSI). Their father had recessively inherited deafness associated with dilated vestibular aqueducts and a clinical diagnosis of Pendred's syndrome was made in him, which was confirmed molecularly. As the twin boys did not have features of WSI, both the mother and children were tested for mutations in SLC26A4 which showed the mother to be a carrier of a single mutation and both boys to be compound heterozygotes, illustrating pseudodominant inheritance of the condition.
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PMID:Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness. 1509 45


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