Limits...
Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report.

Jamsheer A, Sowińska A, Kaczmarek L, Latos-Bieleńska A - BMC Med. Genet. (2012)

Bottom Line: So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE.The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE.We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University of Medical Sciences in Poznan, Poland, ul. Grunwaldzka 55 paw. 15, 60-352 Poznan, Poland. jamsheer@wp.pl

ABSTRACT

Background: Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene. Since the initial manuscript, one further HOXD13 mutation has been reported only in a single family manifesting isolated BDE.

Case presentation: In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene. So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.

Conclusion: The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.

Show MeSH

Related in: MedlinePlus

Schematic presentation of the HOXD13 gene structure and overview of all annotated HOXD13 mutations identified in patients affected by various limb malformations. Arrows indicate approximate positions of HOXD13 mutations. Numbers below or above each arrow refer to specific mutations and correspond to the numbers provided in the table below. Different designations have been used to discriminate between types of mutations: arrows above the exons indicate mutations causing BDE, BD-syndactyly, and syndactyly type V (white, grey, and black arrows respectively); arrows below the exons show mutations resulting in SPD or unspecified limb phenotype (black and grey arrows respectively). Mutation p.R274X identified in our proband (number 18) has been bolded and highlighted with large arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3278352&req=5

Figure 2: Schematic presentation of the HOXD13 gene structure and overview of all annotated HOXD13 mutations identified in patients affected by various limb malformations. Arrows indicate approximate positions of HOXD13 mutations. Numbers below or above each arrow refer to specific mutations and correspond to the numbers provided in the table below. Different designations have been used to discriminate between types of mutations: arrows above the exons indicate mutations causing BDE, BD-syndactyly, and syndactyly type V (white, grey, and black arrows respectively); arrows below the exons show mutations resulting in SPD or unspecified limb phenotype (black and grey arrows respectively). Mutation p.R274X identified in our proband (number 18) has been bolded and highlighted with large arrow.

Mentions: HOXD13 is a member of a large family of developmental homeobox transcription factor genes. Human, as well as other vertebrate genomes contain 39 HOX genes organized into four clusters (HOXA, HOXB, HOXC, and HOXD). HOX genes are involved in body plan formation and embryonic development of many internal organs, such as central nervous system, gastrointestinal and genitourinary tract. They also play a critical role in limb development by influencing limb patterning along proximodistal and anteroposterior axes. In general, the position of the gene in each cluster corresponds to its spatio-temporal expression during limb development in an order from 3' to 5' end. Thus, homologues located at the 3' end of the cluster are expressed earlier in development and in more proximal and anterior structures, whereas those located at the 5' end are expressed later and in more posterior and distal embryonic regions [7,8]. The HOXD13 gene consists of two exons and encodes a protein built of 335 amino acids. Exon 1 contains an N-terminal tract comprised of 15 polyalanine residues in wild-type protein. Exon 2 carries a sequence for a highly conserved C-terminal DNA binding domain, known as homeodomain, through which HOXD13 interacts with consensus DNA sequence. A schematic view of the protein structure and a summary of annotated mutations are given in Figure 2.


Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report.

Jamsheer A, Sowińska A, Kaczmarek L, Latos-Bieleńska A - BMC Med. Genet. (2012)

Schematic presentation of the HOXD13 gene structure and overview of all annotated HOXD13 mutations identified in patients affected by various limb malformations. Arrows indicate approximate positions of HOXD13 mutations. Numbers below or above each arrow refer to specific mutations and correspond to the numbers provided in the table below. Different designations have been used to discriminate between types of mutations: arrows above the exons indicate mutations causing BDE, BD-syndactyly, and syndactyly type V (white, grey, and black arrows respectively); arrows below the exons show mutations resulting in SPD or unspecified limb phenotype (black and grey arrows respectively). Mutation p.R274X identified in our proband (number 18) has been bolded and highlighted with large arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3278352&req=5

Figure 2: Schematic presentation of the HOXD13 gene structure and overview of all annotated HOXD13 mutations identified in patients affected by various limb malformations. Arrows indicate approximate positions of HOXD13 mutations. Numbers below or above each arrow refer to specific mutations and correspond to the numbers provided in the table below. Different designations have been used to discriminate between types of mutations: arrows above the exons indicate mutations causing BDE, BD-syndactyly, and syndactyly type V (white, grey, and black arrows respectively); arrows below the exons show mutations resulting in SPD or unspecified limb phenotype (black and grey arrows respectively). Mutation p.R274X identified in our proband (number 18) has been bolded and highlighted with large arrow.
Mentions: HOXD13 is a member of a large family of developmental homeobox transcription factor genes. Human, as well as other vertebrate genomes contain 39 HOX genes organized into four clusters (HOXA, HOXB, HOXC, and HOXD). HOX genes are involved in body plan formation and embryonic development of many internal organs, such as central nervous system, gastrointestinal and genitourinary tract. They also play a critical role in limb development by influencing limb patterning along proximodistal and anteroposterior axes. In general, the position of the gene in each cluster corresponds to its spatio-temporal expression during limb development in an order from 3' to 5' end. Thus, homologues located at the 3' end of the cluster are expressed earlier in development and in more proximal and anterior structures, whereas those located at the 5' end are expressed later and in more posterior and distal embryonic regions [7,8]. The HOXD13 gene consists of two exons and encodes a protein built of 335 amino acids. Exon 1 contains an N-terminal tract comprised of 15 polyalanine residues in wild-type protein. Exon 2 carries a sequence for a highly conserved C-terminal DNA binding domain, known as homeodomain, through which HOXD13 interacts with consensus DNA sequence. A schematic view of the protein structure and a summary of annotated mutations are given in Figure 2.

Bottom Line: So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE.The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE.We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, University of Medical Sciences in Poznan, Poland, ul. Grunwaldzka 55 paw. 15, 60-352 Poznan, Poland. jamsheer@wp.pl

ABSTRACT

Background: Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the HOXD13 gene. Since the initial manuscript, one further HOXD13 mutation has been reported only in a single family manifesting isolated BDE.

Case presentation: In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous HOXD13 mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the HOXD13 gene. So far, only two missense HOXD13 substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.

Conclusion: The variant p.R274X identified in our proband is the fourth HOXD13 mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described HOXD13 associated phenotypes and mutations.

Show MeSH
Related in: MedlinePlus