title: Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q.
abstract: Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown. Here, we report mouse Recombination-induced mutation 4 (Rim4) as a model animal of 4q+. The Rim4 genome contains an insertion of a 6.5 Mb fragment from mouse chromosome 8 into chromosome 6. This insertion fragment contains 17 genes, including Hand2, that encode the basic helix-loop-helix transcription factor and is syntenic to the distal end of human Chr4, 4q32.3 to 4q34.1, which is responsible for 4q+. A comparison of phenotypes between patients with Rim4 and 4q+ revealed that Rim4 shows direct parallels with many phenotypes of 4q+ such as craniofacial, heart, cervical vertebra and limb deformities. Rebalancing the gene dosage by a genetic cross with Hand2 knockout mice ameliorated symptoms of the heart and limb deformities of Rim4. Conversely, an increase in copy number of Hand2 in wild-type mice recaptures the heart and limb deformities of Rim4. Our results collectively demonstrate that overdosage of Hand2 is a major cause for at least the limb and heart phenotypes of 4q+ and that mouse Rim4 provides a unique animal model for understanding the molecular bases underlying the complex phenotypes of 4q+.
authors: Genetic Strains Research Center, Mammalian Genetics Laboratory, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
authors: Masaru
authors: M
authors: Tamura
authors: Masaki
authors: M
authors: Hosoya
authors: Motoi
authors: M
authors: Fujita
authors: Tomoko
authors: T
authors: Iida
authors: Takanori
authors: T
authors: Amano
authors: Akiteru
authors: A
authors: Maeno
authors: Taro
authors: T
authors: Kataoka
authors: Taketo
authors: T
authors: Otsuka
authors: Shigekazu
authors: S
authors: Tanaka
authors: Shuichi
authors: S
authors: Tomizawa
authors: Toshihiko
authors: T
authors: Shiroishi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004195:Disease Models, Animal; D005121:Extremities / Q000254:growth & development; D005260:Female; D018628:Gene Dosage; D006321:Heart / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014314:Trisomy / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C498765:HAND2 protein, human; C498766:Hand2 protein, mouse