HGNC Approved Gene Symbol: GDF1
SNOMEDCT: 26146002, 7484005, 86299006; ICD10CM: Q20.1, Q20.3, Q21.3; ICD9CM: 745.1, 745.10, 745.11, 745.2;
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:18,868,545-18,896,158 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.11 | Congenital heart defects, multiple types, 6 | 613854 | Autosomal dominant | 3 |
| Right atrial isomerism (Ivemark) | 208530 | Autosomal recessive | 3 |
The transforming growth factor-beta (TGF-beta) superfamily contains a group of proteins likely to play critical roles in regulating differentiation events during embryonic development. Lee (1990) identified a mouse embryo cDNA encoding an additional TGF-beta family member that he called GDF1. Using mouse GDF1 cDNA as a probe, Lee (1991) isolated cDNAs encoding human GDF1. The sequence of the predicted 372-amino acid human protein shares 69% identity with that of mouse GDF1. In both human and mouse GDF1, the TGF-beta homologous region is C-terminal to a pair of basic residues which represent a putative site of proteolytic processing. Northern blot analysis detected mouse GDF1 expression as 1.4- and 3-kb mRNAs. The shorter transcript disappeared after day 10.5 of gestation. The 3-kb mRNA, expressed specifically in the nervous system, appeared at 9.5 days and persisted throughout development. In the human cDNA and the mouse cDNA corresponding to the 3-kb transcript there was a second upstream open reading frame, which Lee (1991) designated UOG1 (LASS1; 606919) for 'upstream of GDF1.'
Rasooly (1998) noted the presence of sequences in GenBank (AC003972) 99% identical to GDF1 within a 1-Mb cloned region surrounding the MEF2B gene (600661) in chromosome 19p12.
Gross (2015) mapped the GDF1 gene to chromosome 19p13.11 based on an alignment of the GDF1 sequence (GenBank AB209169) with the genomic sequence (GRCh38).
Multiple Types of Congenital Heart Disease 6
Karkera et al. (2007) performed a mutation screen of the GDF1 gene in 375 unrelated individuals with a multiple types of congenital cardiovascular malformations (CHTD6; 613854), a group of 225 normal controls, and 198 patients with holoprosencephaly. Mutations were found in GDF1 only in the cardiovascular malformation group (see, e.g., 602880.0001-602880.0003). Karkera et al. (2007) showed that heterozygous loss-of-function mutations in the GDF1 gene contribute to cardiac defects ranging from tetralogy of Fallot to transposition of the great arteries and suggested that decreased TGF-beta (190180) signaling provides a framework for understanding their pathogenesis. These findings implicated perturbations of the TGF-beta signaling pathway in the causation of a major subclass of human congenital heart defects.
In 10 probands with multiple types of congenital heart defects, including conotruncal cardiac defects and heterotaxy, Jin et al. (2017) identified homozygosity for the same missense mutation in the GDF1 gene (M364T; 602880.0006). Principal component analysis of their genotypes showed that all M364T homozygotes clustered with Ashkenazim.
Right Atrial Isomerism
In 5 affected sibs in a Finnish family with right atrial isomerism (RAI; 208530), Kaasinen et al. (2010) detected compound heterozygosity for a nonsense (C227X; 602880.0001) and a frameshift (c.909insC; 602880.0004) mutation in the GDF1 gene.
In a patient with right isomerism, Jin et al. (2017) identified compound heterozygosity for mutations in the GDF1 gene: C227X and a 4-bp deletion (602880.0005).
Rankin et al. (2000) showed that at early stages of mouse development, Gdf1 is expressed initially throughout the embryo proper and then most prominently in the primitive node, ventral neural tube, and intermediate and lateral plate mesoderm. To examine its biologic function, they generated a mouse line carrying a targeted mutation in Gdf1. Gdf1 -/- mice exhibited a spectrum of defects related to left-right axis formation, including visceral situs inversus, right pulmonary isomerism, and a range of cardiac anomalies. The authors suggested that Gdf1 acts upstream of Lefty1 (603037), Lefty2 (601877), Nodal (601265), and Pitx2 (601542) either directly or indirectly to activate their expression. The findings suggested that Gdf1 acts early in the pathway of gene activation that leads to the establishment of left-right asymmetry.
Murine Gdf1 is upstream of a cascade of left-sided determinants that participate in the establishment and maintenance of left-right signals governing asymmetric organogenesis, including the heart and great vessels (Rankin et al., 2000; Wall et al., 2000). Pitx2 (601543) is one such asymmetrically expressed downstream target of the left-right cascade, and, in mice, loss of function of this bicoid-class transcription factor by gene targeting causes transposition of the great arteries (the most common form of which is 'dextro-looped TGA'), double-outlet right ventricle (DORV), persistent truncus arteriosus, and atrial isomerism (Franco and Campione, 2003). Karkera et al. (2007) stated that these observations strengthen the hypothesis that left-right patterning signals can directly or indirectly affect cardiac development and could help explain congenital heart defect manifestations in humans.
Transposition of the Great Arteries
In a patient with transposition of the great arteries (CHDT6; 613854), Karkera et al. (2007) found heterozygous substitution of a stop codon for cys227 of the GDF1 proprotein (C227X). The mutation was considered a likely loss-of-function change because of premature termination in the prodomain.
Right Atrial Isomerism
In 5 affected sibs in a Finnish family with right atrial isomerism (RAI; 208530), originally reported by Eronen et al. (2004), Kaasinen et al. (2010) compound heterozygosity for mutations in the GDF1 gene: a c.681C-A transversion in exon 8, resulting in the C22X substitution, and a 1-bp insertion in exon 8 (c.909insC; 602880.0004), causing a frameshift predicted to result in a severely altered protein and premature termination. Their unaffected parents were each heterozygous for 1 of the mutations.
In a patient (1-05386) with right isomerism, Jin et al. (2017) identified compound heterozygosity for the C22X mutation and a 3-bp deletion (c.1090_1092delATG) in the GDF1 gene, resulting in deletion of the Met364 residue (Met364del; 602880.0005). The patient exhibited abdominal heterotaxy as well as multiple cardiac anomalies, including dextrocardia, double-outlet right ventricle, obstructed total anomalous pulmonary venous return, valvular and subvalvular pulmonary stenosis, persistent left superior vena cava, right-dominant atrioventricular canal, common atrium, and single ventricle.
In a patient with double-outlet right ventricle and stenosis of the left pulmonary artery (CHTD6; 613854), Karkera et al. (2007) identified heterozygosity for a cys267-to-tyr (C267Y) substitution in the GDF1 proprotein, corresponding to a C14Y change in the mature protein that eliminates 1 of the 6 cysteines crucial for the formation of the cystine knot. Functional analysis in zebrafish showed significantly attenuated activity with the mutant compared to wildtype GDF1, consistent with the mutation representing a hypomorphic or loss-of-function allele.
In a patient with tetralogy of Fallot (CHTD6; 613854), Karkera et al. (2007) identified heterozygosity for a gly162-to-asp (G162D) substitution in the prodomain. The authors stated that the mutation could not be evaluated either structurally or functionally.
For discussion of the 1-bp insertion (c.909insC) in exon 8 of the GDF1 gene, causing a frameshift resulting in a severely altered protein and truncation, that was found in compound heterozygous state in a patient with right atrial isomerism (208530) by Kaasinen et al. (2010), see 602880.0001.
For discussion of the 3-bp deletion (c.1090_1092delATG) in the GDF1 gene, resulting in deletion of the met364 residue, that was found in compound heterozygous state in a patient with right atrial isomerism (RAI; 208530) by Jin et al. (2017), see 602880.0001.
In 10 probands with multiple types of congenital heart defects (CHTD6; 613854), Jin et al. (2017) identified homozygosity for a c.1091T-C transition in the GDF1 gene, resulting in a met364-to-thr (M364T) substitution. Other features reported in these patients included neurodevelopmental disorders (types not specified) in 3 of the probands. Principal component analysis of the WES genotypes showed that all M364T homozygotes clustered with Ashkenazim and exhibited a shared haplotype of widely varying length, indicating remote shared ancestry that was inferred to have occurred 50 generations earlier. Among 302 Ashkenazi autism parent controls and 926 additional Ashkenazi adults without congenital heart disease, the variant was present at a carrier frequency of 1.0%; the variant was not found in African, Asian, or Finnish populations in the ExAC database.
Eronen, M., Kajantie, E., Boldt, T., Pitkanen, O., Aittomaki, K. Right atrial isomerism in four siblings. Pediat. Cardiol. 25: 141-144, 2004. [PubMed: 14648004] [Full Text: https://doi.org/10.1007/s00246-003-0540-1]
Franco, D., Campione, M. The role of Pitx2 during cardiac development: linking left-right signaling and congenital heart diseases. Trends Cardiovasc. Med. 13: 157-163, 2003. [PubMed: 12732450] [Full Text: https://doi.org/10.1016/s1050-1738(03)00039-2]
Gross, M. B. Personal Communication. Baltimore, Md. 1/29/2015.
Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton, S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., and 33 others. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nature Genet. 49: 1593-1601, 2017. [PubMed: 28991257] [Full Text: https://doi.org/10.1038/ng.3970]
Kaasinen, E., Aittomaki, K., Eronen, M., Vahteristo, P., Karhu, A., Mecklin, J.-P., Kajantie, E., Aaltonen, L. A., Lehtonen, R. Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1). Hum. Molec. Genet. 19: 2747-2753, 2010. [PubMed: 20413652] [Full Text: https://doi.org/10.1093/hmg/ddq164]
Karkera, J. D., Lee, J. S., Roessler, E., Banerjee-Basu, S., Ouspenskaia, M. V., Mez, J., Goldmuntz, E., Bowers, P., Towbin, J., Belmont, J. W., Baxevanis, A. D., Schier, A. F., Muenke, M. Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am. J. Hum. Genet. 81: 987-994, 2007. [PubMed: 17924340] [Full Text: https://doi.org/10.1086/522890]
Lee, S.-J. Identification of a novel member (GDF-1) of the transforming growth factor-beta superfamily. Molec. Endocr. 4: 1034-1040, 1990. [PubMed: 1704486] [Full Text: https://doi.org/10.1210/mend-4-7-1034]
Lee, S.-J. Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proc. Nat. Acad. Sci. 88: 4250-4254, 1991. [PubMed: 2034669] [Full Text: https://doi.org/10.1073/pnas.88.10.4250]
Rankin, C. T., Bunton, T., Lawler, A. M., Lee, S.-J. Regulation of left-right patterning in mice by growth/differentiation factor-1. Nature Genet. 24: 262-265, 2000. [PubMed: 10700179] [Full Text: https://doi.org/10.1038/73472]
Rasooly, R. S. Personal Communication. Baltimore, Md. 7/13/1998.
Wall, N. A., Craig, E. J., Labosky, P. A., Kessler, D. S. Mesendoderm induction and reversal of left-right pattern by mouse Gdf1, a Vg1-related gene. Dev. Biol. 227: 495-509, 2000. [PubMed: 11071769] [Full Text: https://doi.org/10.1006/dbio.2000.9926]