title: Linkage analysis of genetic loci for kyphoscoliosis on chromosomes 5p13, 13q13.3, and 13q32.
abstract: Kyphoscoliosis, a three-dimensional deformity of spinal growth, is characterized by a curvature in the coronal plane (scoliosis) in conjunction with thoracic kyphosis in excess of the normal range in the sagittal plane. We identified kyphoscoliosis within members of seven families (53 individuals) originally ascertained as part of a large collaborative study of familial idiopathic scoliosis. Model-independent linkage analysis of a genome-wide microsatellite screen identified areas suggestive of linkage on chromosomes 2q22, 5p13, 13q, and 17q11. Single-point and multipoint analyses of an additional 25 flanking microsatellite markers corroborated linkage to these regions, with areas on chromosomes 5p13, 13q13, and 13q32 being the most significant (P < 0.005). Analyses of single nucleotide polymorphism (SNP) markers in the candidate region on chromosome 5 narrowed the region to approximately 3.5 Mb (P < 0.05), with the most significant P values (P < 0.01) occurring in approximately a 1.3-Mb region. Candidate loci in this region include IRX1, IRX2, and IRX4 of the Iroquois Homeobox protein family. On chromosome 13, single-point and multipoint analyses resulted in multiple SNPs having P values < 0.05 within five candidate genes: Osteoblast-specific factor 2 or periostin, forkhead box O1A, A-kinase anchor protein 11, TBC1 domain family member 4, and glypican 5, thus supporting the potential relevance of this region in the pathogenesis of kyphoscoliosis.
authors.affiliation: Department of Orthopaedic Surgery, Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. nmillerb@jhmi.edu
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Miller
authors.forename: Beth
authors.initials: B
authors.lastname: Marosy
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Justice
authors.forename: Steven M
authors.initials: SM
authors.lastname: Novak
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Tang
authors.forename: Paul
authors.initials: P
authors.lastname: Boyce
authors.forename: James
authors.initials: J
authors.lastname: Pettengil
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007738:Kyphosis / Q000150:complications / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D012600:Scoliosis / Q000150:complications / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C501591:IRX1 protein, human; C501595:IRX2 protein, human; C485533:IRX4 protein, human; D014157:Transcription Factors