title: A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease.
abstract: Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched "claw foot" appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T-->A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; theta =0), and it very likely accounts for both CVT and CMT in heterozygotes.
authors.affiliation: Department of Clinical Pathology, State University of New York, Upstate Medical University, Syracuse, 13210, USA. shrimpta@upstate.edu
authors.forename: Antony E
authors.initials: AE
authors.lastname: Shrimpton
authors.forename: E Mark
authors.initials: EM
authors.lastname: Levinsohn
authors.forename: Justin M
authors.initials: JM
authors.lastname: Yozawitz
authors.forename: David S
authors.initials: DS
authors.lastname: Packard
authors.forename: Robert B
authors.initials: RB
authors.lastname: Cady
authors.forename: Frank A
authors.initials: FA
authors.lastname: Middleton
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
authors.forename: David R
authors.initials: DR
authors.lastname: Hootnick
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D008040:Genetic Linkage; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009518:New York; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D013628:Talus / Q000002:abnormalities*; D014157:Transcription Factors / Q000235:genetics*; D029961:Zebrafish Proteins
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C099223:hoxd10a protein, zebrafish; C072064:HOXD10 protein, human