Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q
| Autor: | Shigekazu Tanaka, Akiteru Maeno, Taro Kataoka, Toshihiko Shiroishi, Takanori Amano, Tomoko Iida, Masaki Hosoya, Motoi Fujita, Taketo Otsuka, Masaru Tamura, Shuichi Tomizawa |
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| Rok vydání: | 2013 |
| Předmět: |
Heart Defects
Congenital Male Gene Dosage Limb Deformities Congenital Chromosome Disorders Trisomy medicine.disease_cause Gene dosage Mice Gene duplication Genetics medicine Basic Helix-Loop-Helix Transcription Factors Animals Humans Craniofacial Molecular Biology Genetics (clinical) Mice Knockout Mutation biology Extremities Heart General Medicine medicine.disease Mice Inbred C57BL Disease Models Animal Chromosome 4 Knockout mouse biology.protein Female Chromosomes Human Pair 4 HAND2 |
| Zdroj: | Human molecular genetics. 22(12) |
| ISSN: | 1460-2083 |
| Popis: | 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+. |
| Databáze: | OpenAIRE |
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