Eight-alanine duplication in homeobox D13 in a Chinese family with synpolydactyly

Qian, Xiaohong; Li, Lin; Li, Jiangxia; Qiu, Rongfang; Guo, Chao-Yu; Gong, Yaoqin; Liu, Qiji

doi:10.1016/j.gene.2012.02.046

Cited by 11 publications

(9 citation statements)

References 14 publications

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“…Poly-Ala tract expansions in transcription factors are commonly associated with birth defects in humans that cause malformations of the brain, digits, limbs, and heart [ 64 ]. For example, homeobox genes involved in the regulation of patterning during limb development can contribute to developmental defects when expansions of their poly-Ala tracts occur above identified thresholds [ 66 ].…”

Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

“…One such gene is homeobox D13 ( HOXD13 ). HOXD13 protein contains a poly-Ala tract in the first exon, which upon expansion above an 8-alanine threshold, is associated with human synpolydactyly (SPD) [ 64 , 65 , 66 ]. SPD is an autosomal-dominant disease resulting in limb malformations, usually including digit duplication [ 64 , 66 ].…”

Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

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Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Darling

Uversky

2017

Molecules

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Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure. However, in some cases, the repetitive mRNAs can be translated in a non-canonical manner, generating highly repetitive peptides of different length and amino acid composition. The repeat extension-caused aggregation of a repetitive protein may represent a pivotal step for its transformation into a proteotoxic entity that can lead to pathology. The goals of this article are to systematically analyze molecular mechanisms of the proteinopathies caused by the poly-glutamine and poly-alanine homorepeat expansion, as well as by the polypeptides generated as a result of the microsatellite expansions in non-coding gene regions and to examine the related proteins. We also present results of the analysis of the prevalence and functional roles of intrinsic disorder in proteins associated with pathological repeat expansions.

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Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

Section: Polyalanine Repeat Expansionsmentioning

confidence: 99%

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Darling

Uversky

2017

Molecules

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“…As previously reported, more than 20 mutations of HOXD13 have been reported to be associated with synpolydactyly (Warren 1997;Goodman et al 1998;Nakano et al 2007;Fantini et al 2009;Wajid et al 2009;Gong et al 2011;Kurban et al 2011;Brison et al 2012;Low and Newbury-Ecob 2012;Wang et al 2012;Xin et al 2012;Zhou et al 2013;Dai et al 2014). Generally, these mutations could be categorized into three classes: polyalanine repeat expansions, truncations, and homeodomain missense.…”

Section: Discussionmentioning

confidence: 88%

Exome sequencing identifies a novel nonsense mutation of HOXD13 in a Chinese family with synpolydactyly

Wang

Niu

Geng

et al. 2017

Congenital Anomalies

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Synpolydactyly (SPD) is an autosomal dominant limb malformation with a distinctive combination of syndactyly and polydactyly. SPD is clinically heterogeneous and could be genetically classified into three types. The clinical phenotype of SPD is complicated by its variable expressivity. In the present study, whole exome sequencing (WES) was used to identify the affected gene(s) in a Chinese family with atypical SPD phenotype. Our results showed that a novel heterogenous nonsense mutation (c.556C > T, p.R186X) in HOXD13 was associated with this SPD case. Due to variable expressivity, the diagnosis of a clinical heterogenous disease such as SPD is usually difficult. Our results also suggested that WES is an efficient tool to assist with these diagnoses.

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“…Goodman et al ( 22 ) observed that the penetrance in 20 typical synpolydactyly pedigrees was positively associated with the severity of limb deformities and the number of alanine residues. Other HOXD13 mutation types have also been associated with synpolydactyly, including nonsense ( 24 , 25 ) and missense ( 12 ) mutations, small deletions, frameshift mutations and splice acceptor mutations ( 17 , 26 , 27 ). From the genotyping results of the microsatellites in these regions, the causative gene in the current pedigree was mapped to 2q31 (type I).…”

Section: Discussionmentioning

confidence: 99%

Functional classification and mutation analysis of a synpolydactyly kindred

Zhou

Chen

Cao

et al. 2014

Experimental and Therapeutic Medicine

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The aim of the present study was to analyze a congenital syndactyly/polydactyly kindred and propose a new functional classification method of clinical significance. The modes of inheritance and mutational mechanisms were also determined using genetic analyses. Hand and foot anatomy and functions were measured using photographic images, X-ray imaging and grip ability tests. Genetic analysis comprised the genotyping of polymorphic microsatellite markers at known polydactyly-associated loci and the sequencing of the candidate gene. A functional classification system was devised to divide the clinical features into three types, which included mild, moderate or severe deformity. The family was concluded to have syndactyly type II with autosomal dominant inheritance. The microsatellites, D2S2310 and D2S2314, at the 2q31–32 chromosome, which have previously been associated with synpolydactyly type I, were found to be associated with the disorder in the current family. A 27-bp insertion mutation was identified in the affected individuals in the HOXD13 gene at this locus. The insertion added a further nine alanine residues to the polyalanine stretch within the encoded protein. In conclusion, the functional classification method described in the present study may be used to guide surgical approaches to treatment. A family was identified in whom expansion of the polyalanine tract in the HOXD13 gene causes autosomal dominant hereditary synpolydactyly.

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Eight-alanine duplication in homeobox D13 in a Chinese family with synpolydactyly

Cited by 11 publications

References 14 publications

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions

Exome sequencing identifies a novel nonsense mutation of HOXD13 in a Chinese family with synpolydactyly

Functional classification and mutation analysis of a synpolydactyly kindred

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