Worldwide Distribution of Waardenburg Syndrome

Nayak, Chetan S.; Isaacson, Glenn

doi:10.1177/000348940311200913

Cited by 82 publications

(76 citation statements)

References 14 publications

(2 reference statements)

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“…4B). This congenital syndrome stems from defects in the developing neural crest and is characterized by craniofacial dysmorphology, abnormal pigmentation, and hearing loss [in fact, it accounts for 2-5% of cases of human deafness (27)]. In particular, this phenolog suggested that a set of three vesicle trafficking genes involved in directing plant growth in response to gravitational cues might also serve to direct neural crest cell migration and differentiation in developing animal embryos.…”

Section: Human/arabidopsis Phenologs Predict Vertebrate Regulators Ofmentioning

confidence: 99%

Systematic discovery of nonobvious human disease models through orthologous phenotypes

McGary

Park

Woods

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

276

280

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Biologists have long used model organisms to study human diseases, particularly when the model bears a close resemblance to the disease. We present a method that quantitatively and systematically identifies nonobvious equivalences between mutant phenotypes in different species, based on overlapping sets of orthologous genes from human, mouse, yeast, worm, and plant (212,542 gene-phenotype associations). These orthologous phenotypes, or phenologs, predict unique genes associated with diseases. Our method suggests a yeast model for angiogenesis defects, a worm model for breast cancer, mouse models of autism, and a plant model for the neural crest defects associated with Waardenburg syndrome, among others. Using these models, we show that SOX13 regulates angiogenesis, and that SEC23IP is a likely Waardenburg gene. Phenologs reveal functionally coherent, evolutionarily conserved gene networks-many predating the plant-animal divergence-capable of identifying candidate disease genes.angiogenesis | bioinformatics | evolution | gene-phenotype associations | homology B iochemical and molecular functions of a given protein are generally conserved between organisms; this observation is fundamental to biological research. For example, in x-ray crystallography studies, one can often choose the organism from which the protein is most easily crystallized to facilitate the study of the protein's biochemical function. On the other hand, even with a conserved gene, disruption of function may give rise to radically different phenotypic outcomes in different species. For example, mutating the human RB1 gene leads to retinoblastoma, a cancer of the retina, yet disrupting the nematode ortholog contributes to ectopic vulvae (1, 2). Thus, although a gene's "molecular" functions are conserved, the "organism-level" functions need not be. When a conserved gene is mutated, the resulting organism-level phenotype is an emergent property of the system. This bedrock principle underlying the use of model organisms not only allows us to study important aspects of human biology using mice or frogs, but also permits exploration of inherently multicellular processes, such as cancer, using unicellular organisms like yeast.Within this paradigm, once a molecular function has been discovered in one organism, it should be predictable in other organisms: GSK3 homologs in yeast are kinases, and such GSK3 homologs in every other organism will generally be kinases. In contrast, the emergent organism-level phenotypes are far less predictable between organisms, in part because relationships between genes and phenotypes are many-to-many. Manipulation of GSK3 perturbs nutrient and stress signaling in yeast, anteroposterior patterning and segmentation in insects, dorsoventral patterning in frogs, and craniofacial morphogenesis in mice (3-5). Recognizing functionally equivalent organism-level phenotypes between model organisms can therefore be nonobvious, especially across large evolutionary distances.However, the ability to recognize equivalent phenotypes betwee...

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Section: Human/arabidopsis Phenologs Predict Vertebrate Regulators Ofmentioning

confidence: 99%

Systematic discovery of nonobvious human disease models through orthologous phenotypes

McGary

Park

Woods

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

276

280

View full text Add to dashboard Cite

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“…WS is an autosomal dominant auditorypigmentation disorder in humans (1 per 40,000 live births) that accounts for 2% of all cases of congenital deafness (12). Several genes have been implicated in the four clinical varieties of WS: Mutations in PAX3 cause WS type 1 and type 3 (13,14) and mutations in SOX10, EDNRB, or EDNR3 cause WS type 4 (15)(16)(17).…”

mentioning

confidence: 99%

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Clark

Wahl

Rees

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

227

242

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Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. This trait is inherited in an autosomal, incompletely dominant fashion. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities, which are similar to those observed for the human auditory-pigmentation disorder Waardenburg syndrome. Mutations in at least five genes have been identified as causative for Waardenburg syndrome; however, the genetic bases for all cases have not been determined. Linkage disequilibrium was identified for a microsatellite marker with the merle phenotype in the Shetland Sheepdog. The marker is located in a region of CFA10 that exhibits conservation of synteny with HSA12q13. This region of the human genome contains SILV, a gene important in mammalian pigmentation. Therefore, this gene was evaluated as a candidate for merle patterning. A short interspersed element insertion at the boundary of intron 10͞exon 11 was found, and this insertion segregates with the merle phenotype in multiple breeds. Another finding was deletions within the oligo(dA)-rich tail of the short interspersed element. Such deletions permit normal pigmentation. These data show that SILV is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems. Although the mutant phenotype of SILV in the human is unknown, these results make it an intriguing candidate gene for human auditory-pigmentation disorders.short interspersed element ͉ pigmentation ͉ linkage disequilibrium

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“…Indeed, the authors have discovered a mutation in the dog SILV gene that is responsible for merle, a color patterning in the coat of various canine breeds. Strikingly, merle dogs exhibit auditory and ophthalmologic abnormalities similar to those observed for the human auditorypigmentation disorder Waardenburg syndrome, which accounts for 2-5% of all human cases of congenital deafness (5).…”

mentioning

confidence: 68%