This report describes a postulated contribution of the human KIF1A gene to some cases of congenital heart disease (CHD). Discovery of a patient with CHD carrying a balanced chromosomal translocation with a breakpoint 5’ of KIF1A led to the hypothesis that KIF1A is overexpressed or misexpressed in this genotype.
KIF1A encodes a member of the kinesin family and functions as an anterograde motor protein that transports organelles along microtubules. KIF1A is implicated in multiple neurological diseases; see MIM:601255. The Drosophila gene unc-104 is the closest fly ortholog to KIF1A, as well as to human kinesins KIF1B and KIF1C; both KIF1B and KIF1C are also implicated in human disease. Loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\unc-104.
None of the human genes orthologous to Dmel\unc-104, KIF1A, KIF1B, nor KIF1C, has been introduced into flies. A tagged UAS construct of the mouse Mmus\Kif1A gene has been introduced into flies and has been used to assess the effects of overexpression of this gene. Expression of Mmus\Kif1A specifically in the heart muscle or in all muscles causes diminishes cardiac contractility, myofibrillar disorganization, and heart valve defects; increased collagen IV deposition in the fibrous network that normally surrounds the fly heart is observed. Expression of this transgene in the fly heart may represent misexpression, since in wild-type animals expression of unc-104 in the heart is very low or undetectable. For the assays used, RNAi-effected knockdown of unc-104 specifically in the heart does not result in a detectable phenotype.
Animals homozygous for the most severe mutations of unc-104 die during the embryonic stage. Less severe mutations survive to the third larval instar; these larvae exhibit locomotor, neuroanatomy and neurophysiology defects. See also the human disease model report ‘synaptic dysfunction, KIF1-related’ (FBhh0000875).
[updated Aug. 2020 by FlyBase; FBrf0222196]
A congenital heart defect is a problem with the structure of the heart; it is the most common type of birth defect. The defects can involve the walls of the heart, the valves of the heart, and the arteries and veins near the heart. They can disrupt the normal flow of blood through the heart: the blood flow can slow down, go in the wrong direction or to the wrong place, or be blocked completely (https://medlineplus.gov/congenitalheartdefects.html).
Defects range from simple, which might cause no problems, to complex, which can cause life-threatening complications. The most serious defects are categorized as critical congenital heart defects (CCHD). CCHD is life threatening and requires intervention in infancy; approximately 18 out of 10,000 babies are born with CCHD (https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/PEHDIC/Pages/Newborn-Screening-for-CCHD.aspx).
Genetic causes of congenital heart disease also account for many of the comorbidities seen with increased frequency in congenital heart disease patients, including neurodevelopmental disability, pulmonary disease, arrhythmia, renal disease, heart failure and an increased incidence of malignancy. (Simmons and Brueckner, 2017; pubmed:28872494).
A number of well studied syndromes, including DiGeorge syndrome, Williams-Beuren syndrome, Alagille syndrome, Noonan syndrome, and Holt-Oram syndrome, include congenital heart defect (Pierpont et al., 2007; pubmed:17519398).
Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. [from MIM:306955; 2018.11.13]
Complex congenital heart disease such as HLHS may arise in a modular fashion, mediated by multiple mutations. (Yagi et al., 2018; pubmed:29569026).
Several studies of hypoplastic left heart syndrome among sibs obtained results most compatible with multifactorial inheritance (Holmes et al., 1974, pubmed:15690347; Brownell and Shokeir, 1976, pubmed:1248182) [from MIM:241550; 2020.08.26]
Analysis of 8 independent hypoplastic left heart syndrome (HLHS) mouse lines showed HLHS is genetically heterogeneous and multigenic in etiology (Liu et al.., 2017; pubmed:28530678). [from MIM:241550; 2020.08.26]
KIF1A encodes a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. [Gene Cards, KIF1A; 2020.08.25]
Many to one: 3 human to 1 Drosophila; the human genes are KIF1A, KIF1B and KIF1C.
High-scoring ortholog of KIF1A; moderate-scoring ortholog of KIF1B and KIF1C (1 Drosophila to 3 human). Dmel\unc-104 shares 55% identity and 68% similarity with KIF1A.
