Alternative titles; symbols
HGNC Approved Gene Symbol: HAND1
Cytogenetic location: 5q33.2 Genomic coordinates (GRCh38) : 5:154,474,972-154,478,227 (from NCBI)
The HAND1 gene encodes a basic helix-loop-helix (bHLH) transcription factor that is essential for mammalian heart development (Reamon-Buettner et al., 2009).
Russell et al. (1997) cloned HAND1 from a human fetal cardiac cDNA library, using the mouse Hand1 sequence as probe. The deduced 215-amino acid protein contains a bHLH region and several potential phosphorylation sites. The mouse and human sequences share 93% overall sequence identity. Northern blot analysis detected a 1.8-kb transcript in adult human heart, but not in brain, placenta, lung, liver, skeletal muscle, kidney, or pancreas.
Knofler et al. (1998) cloned HAND1 from a heart-specific cDNA library screened with a HAND1-specific cDNA fragment originally obtained by RT-PCR of human choriocarcinoma cell line mRNA. The sequence predicts a protein calculated to have a molecular mass of 23.6 kD. In vitro translation results in a 29-kD protein, suggesting posttranslational modification. Knofler et al. (1998) confirmed expression of HAND1 in heart and also identified abundant expression in cytotrophoblastic cell lines. Knofler et al. (2002) found that HAND1 mRNA is specifically expressed in amniotic cells at different stages of gestation and demonstrated that the protein is exclusively produced in the amniotic epithelium in vivo and in purified amnion cells in vitro. RT-PCR and immunohistochemical staining of blastocysts revealed the production of HAND1 mRNA and polypeptide in the trophectodermal cell layer.
In mouse, Hand1 and Hand2 (602407) are expressed in the heart and certain neural crest derivatives during embryogenesis. In addition, Hand1 is expressed in extraembryonic membranes, whereas Hand2 is expressed in the deciduum (Cserjesi et al., 1995; Srivastava et al., 1995).
Knofler et al. (2002) found that human HAND1 can stimulate transcriptional activity of E12/E47 (147141) through degenerate E-boxes (the palindromic sequence CANNTG), or inhibit E12/E47 transcriptional activity through perfect E-boxes. By mutation analysis, they determined that 2 regions within the N terminus confers the repressor activity.
Knofler et al. (1998) determined that the HAND1 gene contains 2 exons spanning 3.3 kb.
By radiation hybrid analysis, Russell et al. (1997) mapped the HAND1 gene to chromosome 5q32.
Reamon-Buettner et al. (2008) sequenced the HAND1 gene in cardiac tissue from 31 unrelated patients with hypoplastic hearts (see 241550), 24 with left-sided hypoplasia and 7 with right-sided. A frameshift mutation (376delG) in the bHLH domain of HAND1 was identified in 24 of 31 hypoplastic ventricles; the mutation was also present in the nonhypoplastic ventricle in 9 patients. The authors noted that other sequence alterations were also found in HAND1, but only 376delG was a predictor for the hypoplastic condition. Examination of 68 formalin-fixed hearts selected for septation defects revealed that only 1, with severe malformations, carried the 376delG frameshift mutation; the mutation was not found in 10 formalin-fixed or 5 frozen normal hearts, or in 100 blood samples from healthy volunteers. Yeast-based assays demonstrated that unlike wildtype HAND1, the 376delG mutant was unable to modulate transcription of reporter constructs containing specific DNA-binding sites. Reamon-Buettner et al. (2008) concluded that HAND1 function is impaired in hypoplastic human hearts.
In tissue samples of human cardiac septal defects, including atrial septal defects (see ASD1, 108800), ventricular septal defects (see VSD1, 614429), and atrioventricular septal defects (see AVSD1, 606215), Reamon-Buettner et al. (2009) detected 32 somatic sequence alterations leading to amino acid changes, of which 12 were in the bHLH domain of the HAND1 gene. These sequence alterations were not detected in 15 normal heart tissue samples, 12 blood samples from congenital heart disease patients, or 100 unrelated normal individuals. Functional studies in yeast and mammalian cells enabled translation of sequence alterations to HAND1 transcriptional activity, which was reduced or abolished by certain somatic mutations. Reamon-Buettner et al. (2009) suggested that HAND1 may also be affected in septation defects of the human hearts, and thus may have a broader role in human heart development and congenital heart disease.
Firulli et al. (1998) generated a germline mutation in the mouse Hand1 gene by replacing the first coding exon with a beta-galactosidase reporter gene. Embryos homozygous for the HAND1 null allele died between embryonic days 8.5 and 9.5 and exhibited yolk sac abnormalities due to a deficiency in extraembryonic mesoderm. Heart development was also perturbed and did not progress beyond the cardiac-looping stage. The results demonstrated important roles for HAND1 in extraembryonic mesodermal and heart development.
Riley et al. (1998) likewise generated Hand1-null mutant mice by gene targeting and found that homozygous mutant embryos arrested with defects in trophoblast giant cell differentiation by embryonic day 7.5 of gestation. This early mortality could be rescued by aggregation of mutant embryos with wildtype tetraploid embryos, which contributed wildtype cells to the trophoblast, but not the embryo. By embryonic day 10.5, however, the Hand1-null fetuses derived from tetraploid chimeras died due to cardiac failure. Their heart tubes showed abnormal looping and ventricular myocardial differentiation. Therefore, Hand1 is essential for differentiation of both trophoblasts and cardiomyocytes, which are embryologically distinct cell lineages.
Cserjesi, P., Brown, D., Lyons, G. E., Olson, E. N. Expression of the novel basic helix-loop-helix gene eHAND in neural crest derivatives and extraembryonic membranes during mouse development. Dev. Biol. 170: 664-678, 1995. [PubMed: 7649392] [Full Text: https://doi.org/10.1006/dbio.1995.1245]
Firulli, A. B., McFadden, D. G., Lin, Q., Srivastava, D., Olson, E. N. Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1. Nature Genet. 18: 266-270, 1998. [PubMed: 9500550] [Full Text: https://doi.org/10.1038/ng0398-266]
Knofler, M., Meinhardt, G., Bauer, S., Loregger, T., Vasicek, R., Bloor, D. J., Kimber, S. J., Husslein, P. Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains. Biochem J. 361: 641-651, 2002. [PubMed: 11802795] [Full Text: https://doi.org/10.1042/0264-6021:3610641]
Knofler, M., Meinhardt, G., Vasicek, R., Husslein, P., Egarter, C. Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart. Gene 224: 77-86, 1998. [PubMed: 9931445] [Full Text: https://doi.org/10.1016/s0378-1119(98)00511-3]
Reamon-Buettner, S., Ciribilli, Y., Inga, A., Borlak, J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts (sic). Hum. Molec. Genet. 17: 1397-1405, 2008. [PubMed: 18276607] [Full Text: https://doi.org/10.1093/hmg/ddn027]
Reamon-Buettner, S. M., Ciribilli, Y., Traverso, I., Kuhls, B., Inga, A., Borlak, J. A functional genetic study identifies HAND1 mutations in septation defects of the human heart. Hum. Molec. Genet. 18: 3567-3578, 2009. [PubMed: 19586923] [Full Text: https://doi.org/10.1093/hmg/ddp305]
Riley, P., Anson-Cartwright, L., Cross, J. C. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nature Genet. 18: 271-275, 1998. [PubMed: 9500551] [Full Text: https://doi.org/10.1038/ng0398-271]
Russell, M. W., Baker, P., Izumo, S. Cloning, chromosomal mapping, and expression of the human eHAND gene. Mammalian Genome 8: 863-865, 1997. [PubMed: 9337404] [Full Text: https://doi.org/10.1007/s003359900596]
Srivastava, D., Cserjesi, P., Olson, E. N. A subclass of bHLH proteins required for cardiac morphogenesis. Science 270: 1995-1999, 1995. [PubMed: 8533092] [Full Text: https://doi.org/10.1126/science.270.5244.1995]