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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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Non parametric linkage analysis reveals a maximum LOD score on chromosome 2q22.3–34 (Z=3.15). This region contains the HOXD13 gene, the cause of SPD.
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Figure 3: Non parametric linkage analysis reveals a maximum LOD score on chromosome 2q22.3–34 (Z=3.15). This region contains the HOXD13 gene, the cause of SPD.

Mentions: SPD is characterized as an autosomal dominant disorder with wide variability in the phenotypic consequence of particular mutations. In addition to reduced penetrance, a number of investigators have observed that carriers of two mutations often have a more severe phenotype than heterozygous carriers. We therefore initially performed parametric linkage analysis under the assumption of a dominant mode of transmission with reduced penetrance. This analysis failed to reveal any regions of linkage. Because of the extensive consanguinity in our pedigree, we considered that a majority of affected individuals may be homozygous carriers, so we performed parametric linkage analysis under a recessive mode of inheritance. This approach also failed to reveal and regions of linkage. Finally, we performed nonparametric linkage analysis which does not rely on a prior assumption of a mode of inheritance and we discovered a significant NPL score at chromosome 2q22.3–34 (Z=3.15) (Fig.3).


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)

Non parametric linkage analysis reveals a maximum LOD score on chromosome 2q22.3–34 (Z=3.15). This region contains the HOXD13 gene, the cause of SPD.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Non parametric linkage analysis reveals a maximum LOD score on chromosome 2q22.3–34 (Z=3.15). This region contains the HOXD13 gene, the cause of SPD.
Mentions: SPD is characterized as an autosomal dominant disorder with wide variability in the phenotypic consequence of particular mutations. In addition to reduced penetrance, a number of investigators have observed that carriers of two mutations often have a more severe phenotype than heterozygous carriers. We therefore initially performed parametric linkage analysis under the assumption of a dominant mode of transmission with reduced penetrance. This analysis failed to reveal any regions of linkage. Because of the extensive consanguinity in our pedigree, we considered that a majority of affected individuals may be homozygous carriers, so we performed parametric linkage analysis under a recessive mode of inheritance. This approach also failed to reveal and regions of linkage. Finally, we performed nonparametric linkage analysis which does not rely on a prior assumption of a mode of inheritance and we discovered a significant NPL score at chromosome 2q22.3–34 (Z=3.15) (Fig.3).

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