Functional classification and mutation analysis of a synpolydactyly kindred

Zhou,Jianda; Chen,Yao; Cao,Ke; Zou,Yonghua; Zhou,Haiyan; Hu,Feng; Ni,Bin; Chen,Yong

doi:10.3892/etm.2014.1957

Functional classification and mutation analysis of a synpolydactyly kindred

Authors:
- Jianda Zhou
- Yao Chen
- Ke Cao
- Yonghua Zou
- Haiyan Zhou
- Feng Hu
- Bin Ni
- Yong Chen
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Affiliations: Department of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Changsha, Hunan 410078, P.R. China
Published online on: September 11, 2014 https://doi.org/10.3892/etm.2014.1957
Pages: 1569-1574

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Abstract

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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1	Temtamy SA and McKusick VA: The genetics of hand malformations. Birth Defects Orig Artic Ser. 14:i–xviii. 1–619. 1978.PubMed/NCBI
2	Mollica F, Volti SL and Sorge G: Autosomal recessive postaxial polydactyly type A in a Sicilian family. J Med Genet. 15:212–216. 1978. View Article : Google Scholar : PubMed/NCBI
3	Al-Qattan MM: Type II familial synpolydactyly: report on two families with an emphasis on variations of expression. Eur J Hum Genet. 19:112–114. 2011. View Article : Google Scholar : PubMed/NCBI
4	Sarfarazi M, Akarsu AN and Sayli BS: Localization of the syndactyly type II (synpolydactyly) locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker. Hum Mol Genet. 4:1453–1458. 1995. View Article : Google Scholar : PubMed/NCBI
5	Debeer P, Schoenmakers EF, Twal WO, et al: The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J Med Genet. 39:98–104. 2002. View Article : Google Scholar : PubMed/NCBI
6	Malik S, Abbasi AA, Ansar M, et al: Genetic heterogeneity of synpolydactyly: a novel locus SPD3 maps to chromosome 14q11.2–q12. Clin Genet. 69:518–524. 2006.PubMed/NCBI
7	Snajdr P, Grim M and Liska F: HOX genes and the limb development in the clinical praxis and in the experiment. Cas Lek Cesk. 149:4–9. 2010.(In Czech).
8	Apiou F, Flagiello D, Cillo C, et al: Fine mapping of human HOX gene clusters. Cytogenet Cell Genet. 73:114–115. 1996. View Article : Google Scholar : PubMed/NCBI
9	Goodman FR and Scambler PJ: Human Hox gene mutations. Clin Genet. 59:1–11. 2001. View Article : Google Scholar
10	Salsi V, Vigano MA, Cocchiarella F, et al: Hoxd13 binds in vivo and regulates the expression of genes acting in key pathways for early limb and skeletal patterning. Dev Biol. 317:497–507. 2008. View Article : Google Scholar : PubMed/NCBI
11	Wang B, Xu B, Cheng Z, et al: A novel non-synonymous mutation in the homeodomain of HOXD-13 causes synpolydactyly in a Chinese family. Clin Chim Acta. 413:1049–1052. 2012. View Article : Google Scholar : PubMed/NCBI
12	Brison N, Debeer P, Fantini S, et al: An N-terminal G11A mutation in HOXD13 causes synpolydactyly and interferes with Gli3R function during limb pre-patterning. Hum Mol Genet. 21:2464–2475. 2012. View Article : Google Scholar : PubMed/NCBI
13	Kurban M, Wajid M, Petukhova L, et al: A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance. J Hum Genet. 56:701–706. 2011. View Article : Google Scholar : PubMed/NCBI
14	D’Esposito M, Morelli F, Acampora D, et al: EVX2, a human homeobox gene homologous to the even-skipped segmentation gene, is localized at the 5′ end of HOX4 locus on chromosome 2. Genomics. 10:43–50. 1991.
15	Muragaki Y, Mundlos S, Upton J and Olsen BR: Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science. 272:548–551. 1996. View Article : Google Scholar : PubMed/NCBI
16	Gong L, Wang B, Wang J, et al: Polyalanine repeat expansion mutation of the HOXD13 gene in a Chinese family with unusual clinical manifestations of synpolydactyly. Eur J Med Genet. 54:108–111. 2011. View Article : Google Scholar : PubMed/NCBI
17	Xin Q, Li L, Li J, et al: Eight-alanine duplication in homeobox D13 in a Chinese family with synpolydactyly. Gene. 499:48–51. 2012. View Article : Google Scholar : PubMed/NCBI
18	Cocquempot O, Brault V, Babinet C and Herault Y: Fork stalling and template switching as a mechanism for polyalanine tract expansion affecting the DYC mutant of HOXD13, a new murine model of synpolydactyly. Genetics. 183:23–30. 2009. View Article : Google Scholar : PubMed/NCBI
19	Tüzel E, Samli H, Kuru I, et al: Association of hypospadias with hypoplastic synpolydactyly and role of HOXD13 gene mutations. Urology. 70:161–164. 2007.PubMed/NCBI
20	Warren ST: Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Science. 275:408–409. 1997. View Article : Google Scholar : PubMed/NCBI
21	Jin H, Lin PF, Wang QM, et al: Synpolydactyly in a Chinese kindred: mutation detection, prenatal ultrasonographic and molecular diagnosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 28:601–605. 2011.(In Chinese).
22	Goodman FR, Mundlos S, Muragaki Y, et al: Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proc Natl Acad Sci USA. 94:7458–7463. 1997. View Article : Google Scholar : PubMed/NCBI
23	Zákány J, Kmita M and Duboule D: A dual role for Hox genes in limb anterior-posterior asymmetry. Science. 304:1669–1672. 2004.PubMed/NCBI
24	Kurban M, Wajid M, Petukhova L, et al: A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance. J Hum Genet. 56:701–706. 2011. View Article : Google Scholar : PubMed/NCBI
25	Low KJ and Newbury-Ecob RA: Homozygous nonsense mutation in HOXD13 underlies synpolydactyly with a cleft. Clin Dysmorphol. 21:141–143. 2012. View Article : Google Scholar : PubMed/NCBI
26	Brison N, Tylzanowski P and Debeer P: Limb skeletal malformations - what the HOX is going on? Eur J Med Genet. 55:1–7. 2012. View Article : Google Scholar : PubMed/NCBI
27	Wajid M, Ishii Y, Kurban M, et al: Polyalanine repeat expansion mutations in the HOXD13 gene in Pakistani families with synpolydactyly. Clin Genet. 76:300–302. 2009. View Article : Google Scholar : PubMed/NCBI