Two novel point mutations in the long‐range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly

Gurnett, Christina A.; Bowcock, Anne M.; Dietz, Frederick R.; Morcuende, José A.; Murray, Jeffrey C.; Dobbs, Matthew B.

doi:10.1002/ajmg.a.31563

Cited by 104 publications

(87 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was shown that five point mutations residing in the highly conserved sequence of ZRS were associated with congenital preaxial polydactyly (Lettice et al 2003;Gurnett et al 2007), mutations in the chicken Lmbr1 are linked to chicken polydactyly (Huang et al 2006), and Shh was responsible for the digit duplication activity in chick embryos (Riddle et al 1993). Unfortunately, we failed to identify any pathogenic mutations of these genes in the SD4 patients from the Chinese family.…”

Section: Resultsmentioning

confidence: 86%

A syndactyly type IV locus maps to 7q36

Sato

Pan

et al. 2007

J Hum Genet

View full text Add to dashboard Cite

Syndactyly occurs as an isolated abnormality or a part of a malformation syndrome. Syndactyly types I, II, III and V have been mapped to chromosomal regions 2q34-q36, 2q31-q32, 6q21-q23.2 and 2q31-q32, respectively, whereas syndactyly type IV (SD4) is extremely rare, and its gene localization has not yet been assigned. The SD4 manifests complete syndactyly of all fingers accompanied with polydactyly, and flexion of the fingers gives the hand a cup-shaped appearance. We performed a linkage and haplotype analysis of a Chinese pedigree with autosomal dominant, non-syndromic SD4 using a set of 406 microsatellite markers. The analysis gave the maximum two-point LOD score of 1.613 at recombination fraction of 0.00 and penetrance of 1.00. Thus, the SD4 locus in the family was likely assigned to a 17.39-cM region at a segment between markers D7S3070 and D7S559 at 7q36, although the LOD score obtained was not high enough to conclude the localization. Analysis of three candidate genes, LMBR1, SHH and ZRS, failed to identify any pathogenic mutations. Our gene mapping may give a clue to identify the putative SD4 gene and provide a better understanding of normal human limb development.

show abstract

Section: Resultsmentioning

confidence: 86%

A syndactyly type IV locus maps to 7q36

Sato

Pan

et al. 2007

J Hum Genet

View full text Add to dashboard Cite

show abstract

“…The Arx GABAergic enhancer represents a good candidate as a noncoding sequence that, when mutated, may lead to Arx-specific silencing restricted to forebrain interneurons, and therefore causes the development of related neuropathological conditions (e.g., epilepsy, mental retardation, and motor deficits). Mutations in the enhancer elements of developmental genes like Shh, Ret, Pitx2, Gli3, and Pax6 have been already described to cause human congenital diseases (Emison et al, 2005;Kleinjan and van Heyningen, 2005;Gurnett et al, 2007). Thus, it would be valuable to perform a mutational screening of this Arx enhancer sequence in those highly related neurological disorders in which mutations in the Arx coding region failed to be identified.…”

Section: Discussionmentioning

confidence: 99%

Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons

Colasante¹,

Collombat²,

Raimondi³

et al. 2008

J. Neurosci.

142

127

View full text Add to dashboard Cite

The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of human ARX ortholog causes neurological disorders including epilepsy, lissencephaly, and mental retardation. We have isolated the mouse Arx endogenous enhancer modules that control its tightly compartmentalized forebrain expression. Interestingly, they are scattered downstream of its coding region and partially included within the introns of the downstream PolA1 gene. These enhancers are ultraconserved noncoding sequences that are highly conserved throughout the vertebrate phylum. Functional characterization of the Arx GABAergic enhancer element revealed its strict dependence on the activity of Dlx transcription factors. Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression, suggesting that Arx is a key mediator of Dlx function. To further elucidate the mechanisms involved, a combination of gain-of-function studies in mutant Arx or Dlx tissues was pursued. This analysis provided evidence that, although Arx is necessary for the Dlx-dependent promotion of interneuron migration, it is not required for the GABAergic cell fate commitment mediated by Dlx factors. Although Arx has additional functions independent of the Dlx pathway, we have established a direct genetic relationship that controls critical steps in the development of telencephalic GABAergic neurons. These findings contribute elucidating the genetic hierarchy that likely underlies the etiology of a variety of human neurodevelopmental disorders.

show abstract

“…31 In previous PPD studies, there are only 13 pedigrees in which the responsible point mutations were identified. 13,16,17,23,25 On the other hand, pathogenic mutations are still remained unidentified in most PPD families. 8,11 -13,23 Furthermore, although the 7 pathogenic point mutations identified in above 13 pedigrees were all located in the ZRS of shh, these mutation sites were scattered in the ZRS and no clustering of mutations toward domain-like structure was evident.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, no known regulatory domain had been defined by bioinformatics method, so far. 13 These information suggested that the network of shh regulation was much complex and is poorly understood. Recently, the copy number variations, such as duplication, has been shown to be the underlying cause for human genetic disorders.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

Wang

et al. 2008

Eur J Hum Genet

View full text Add to dashboard Cite

Mutations in the long-range limb-specific cis-regulator (ZRS) could cause ectopic shh gene expression and are responsible for preaxial polydactyly (PPD). In this study, we analyzed a large Chinese isolated autosomal dominant PPD pedigree. By fine mapping and haplotype construction, we located the linked region to a 1.7 cM interval between flanking markers D7S2465 and D7S2423 of chromosome 7q36. We directly sequenced the candidate loci in this linked region, including the coding regions of the five genes (HLXB9, LMBR1, NOM1, RNF32 and C7orf13), the regulatory element (ZRS) of shh, the whole intron 5 of LMBR1 which contained the ZRS, and 18 conserved noncoding sequences (CNSs). Interestingly, no pathogenic mutation was identified. By using real-time quantitative PCR (qPCR), we also excluded the ZRS duplication in this pedigree. Our results indicate that, at least, it is not the mutation in a functional gene, CNS region or duplication of ZRS that cause the phenotype of this pedigree. The etiology of this PPD family still remains unclear and the question whether another limb-specific regulatory element of shh gene exists in the noncoding region in this 1.7 cM interval remains open for future research.

show abstract

Two novel point mutations in the long‐range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly

Cited by 104 publications

References 21 publications

A syndactyly type IV locus maps to 7q36

A syndactyly type IV locus maps to 7q36

Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons

Mutation analysis of a large Chinese pedigree with congenital preaxial polydactyly

Contact Info

Product

Resources

About