ClinVar Genomic variation as it relates to human health

In affected individuals from a large Lebanese kindred segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), originally described by Stephan (1978), Liu et al. (2010) identified heterozygosity for a 1294G-A transition (c.1294G-A, ENST00000252826) (as noted in their Figure 3) in exon 11 of the TRPM4 gene, resulting in an ala432-to-thr (A432T) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete right bundle branch block (RBBB) or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. In a 38-year-old Turkish man with first-degree atrioventricular conduction block and atypical RBBB, Stallmeyer et al. (2012) identified compound heterozygosity for the A432T mutation and a 1744G-A transition in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution (606936.0005) that was not found in 670 European or 154 Turkish control samples. In addition, he carried a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del). His father and a sister had both died suddenly due to cardiac arrhythmias of unknown origin. Xian et al. (2018) found that plasma membrane expression levels of human TRPM4 with the A432T mutation were 50% lower in HEK293 cells, but the relative membrane current was more than 2-fold larger, compared with wildtype TRPM4. Kinetic analysis showed that TRPM4-A432T had 4-fold slower calcium-dependent deactivation than wildtype. Analysis with human induced pluripotent stem cell-derived cardiac myocytes revealed that TRPM4-A432T also generated excessive membrane currents during cardiac action potentials. The authors demonstrated that altered deactivation of TRPM4-A432T was not due to alterations in glycosylation, phosphorylation, or plasma membrane phosphatidylinositol 4,5-bisphosphate levels. Instead, site-directed mutagenesis and structural modeling showed that replacement of the nonpolar, small-side-chained ala432 with a bulky threonine changed the compactness of the channel subdomain in TRPM-A432T. (less)