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A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance.

Kurban M, Wajid M, Petukhova L, Shimomura Y, Christiano AM - J. Hum. Genet. (2011)

Bottom Line: All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation.Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance.Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ∼50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

ABSTRACT
Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant-negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated as Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ∼50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals.

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Pedigree of a Pakistani family with with SPD consistent with an autosomal dominant pattern with incomplete penetrance. Individuals with  and  carry the mutation but are not affected. Individuals (a–i) are homozygous for the mutation and individuals (j–l) are heterozygous for the mutation.
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Figure 1: Pedigree of a Pakistani family with with SPD consistent with an autosomal dominant pattern with incomplete penetrance. Individuals with and carry the mutation but are not affected. Individuals (a–i) are homozygous for the mutation and individuals (j–l) are heterozygous for the mutation.

Mentions: We studied a large consanguineous family from Pakistan with SPD. The inheritance pattern could be explained either by autosomal recessive or autosomal dominant with incomplete penetrance (Fig.1). The clinical presentation among the family members was highly variable. Of 16 affected individuals analyzed, the clinical features of 10 members showed a typical SPD1 phenotype, consisting of syndactyly between the 3/4 fingers with digital duplication, widely spaced 1st and 2nd toes, syndactyly involving toes 2/3/4/5 or 3/4/5, camptodactyly of the big toe and brachydactyly which mainly affected the second toe (Fig.2). On the other hand, remaining 6 affected individuals showed a milder phenotype which was restricted to the toes and consisted mainly of webbing of the 4th and the 5th digits or the 2nd and 3rd digits. In addition, a few affected individuals also had unilateral broad big toes, which is not a typical feature for SPD1 (Fig.2). None of the individuals had any urogenital abnormalities.


A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance.

Kurban M, Wajid M, Petukhova L, Shimomura Y, Christiano AM - J. Hum. Genet. (2011)

Pedigree of a Pakistani family with with SPD consistent with an autosomal dominant pattern with incomplete penetrance. Individuals with  and  carry the mutation but are not affected. Individuals (a–i) are homozygous for the mutation and individuals (j–l) are heterozygous for the mutation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4296310&req=5

Figure 1: Pedigree of a Pakistani family with with SPD consistent with an autosomal dominant pattern with incomplete penetrance. Individuals with and carry the mutation but are not affected. Individuals (a–i) are homozygous for the mutation and individuals (j–l) are heterozygous for the mutation.
Mentions: We studied a large consanguineous family from Pakistan with SPD. The inheritance pattern could be explained either by autosomal recessive or autosomal dominant with incomplete penetrance (Fig.1). The clinical presentation among the family members was highly variable. Of 16 affected individuals analyzed, the clinical features of 10 members showed a typical SPD1 phenotype, consisting of syndactyly between the 3/4 fingers with digital duplication, widely spaced 1st and 2nd toes, syndactyly involving toes 2/3/4/5 or 3/4/5, camptodactyly of the big toe and brachydactyly which mainly affected the second toe (Fig.2). On the other hand, remaining 6 affected individuals showed a milder phenotype which was restricted to the toes and consisted mainly of webbing of the 4th and the 5th digits or the 2nd and 3rd digits. In addition, a few affected individuals also had unilateral broad big toes, which is not a typical feature for SPD1 (Fig.2). None of the individuals had any urogenital abnormalities.

Bottom Line: All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation.Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance.Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ∼50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

ABSTRACT
Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant-negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated as Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ∼50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals.

Show MeSH
Related in: MedlinePlus