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+.

Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration

“…Together, our data suggest that hand2 can play important and instructive roles in elevating cardiomyocyte production in multiple contexts: by promoting specification of FHF cardiomyocytes, by enhancing proliferation of SHF cardiac progenitors and by augmenting proliferation of regenerating cardiomyocytes. These results refine our understanding of the origins of CHD, particularly in the context of partial trisomy distal 4q, which involves duplication of HAND2 (Tamura et al, 2013). Moreover, our findings highlight ways in which hand2 overexpression could facilitate future approaches for cardiac regeneration and repair.…”

“…Duplications and deletions of the 4q33 chromosomal region, which contains HAND2, have been associated with CHD (Borochowitz et al, 1997;Byatt et al, 1997). Moreover, individuals with partial trisomy distal 4q (4q+ syndrome), a translocation that involves duplication of HAND2 and neighboring genes, exhibit striking cardiac and limb defects (Tamura et al, 2013). In a mouse model for 4q+ syndrome, rebalancing levels of Hand2 by breeding to Hand2-deficient animals ameliorated the heart and limb phenotypes, implicating overexpression of Hand2 as a cause of these defects (Tamura et al, 2013).…”

“…Moreover, individuals with partial trisomy distal 4q (4q+ syndrome), a translocation that involves duplication of HAND2 and neighboring genes, exhibit striking cardiac and limb defects (Tamura et al, 2013). In a mouse model for 4q+ syndrome, rebalancing levels of Hand2 by breeding to Hand2-deficient animals ameliorated the heart and limb phenotypes, implicating overexpression of Hand2 as a cause of these defects (Tamura et al, 2013). Our data suggest possible ways in which HAND2 overexpression could cause CHD through alteration of cardiomyocyte production; future studies that elucidate the specific Hand2 partners and targets involved in FHF specification, SHF proliferation and cardiomyocyte proliferation will provide a deeper understanding of the mechanisms through which Hand2 influences the origins of CHD.…”

Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature

“…Mice with abnormalities in this gene die from blood circulation failure [26]. From mouse and zebrafish experiments, HAND2 is also involved in cardiac morphogenesis, angiogenesis, and formation of the right ventricle and aortic arch arteries and, interestingly, plays a role in limb formation [27,28]. Although many individuals presented digital and forearm deficiencies, we were not able to clearly map these phenotypes to this region as well.…”

Automatic classification framework for ventricular septal defects: a pilot study on high-throughput mouse embryo cardiac phenotyping

“…There were 15 mouse embryos collected in this study, consisting of 3 healthy wild-type C57BL/10 samples and 12 mutant subjects through recombination-induced mutation 4 (Rim4). 41 Among the mutants, three were homozygotes, which were generated by inbreeding the Rim4 mouse lines, whereas the remaining nine were heterozygotes, generated by cross-breeding between the wild-type and Rim4 populations. An expert manual assessment via histological examination was carried out, and all three homozygous samples were confirmed to be VSD positive, while all the heterozygous and wild-type subjects were VSD negative.…”