Identification of a new lamin A/C mutation in a chinese family affected with atrioventricular block as the prominent phenotype

Abstract

Even though mutations in LMNA have been reported in patients with typical dilated cardiomyopathy (DCM) and atrioventricular block (AVB) previously, the purpose of this study was to disclose this novel genetic abnormality in one Chinese family with the atypical phenotype of progressive AVB followed by DCM with normal QRS interval. Genome-wide linkage analysis mapped the AVB gene in this family to a marker at chromosome 1q21.2, where the LMNA gene was located. Direct DNA sequence analysis revealed a heterozygous G to A transition at nucleotide 244 in exon 1 of LMNA, which resulted in an E82K mutation. The E82K mutation co-segregated with all affected individuals in the family, and was not present in 200 normal controls. Further clinical evaluation of mutation carriers showed that 5 of 6 AVB patients exhibited mild DCM with a late onset of age in the fourth and fifth decades. Ejection fractions were documented in 5 patients with DCM, but 4 showed a normal value of > or = 50%. Echocardiography showed that atrial dilatation occurred earlier than ventricular dilatation in the patients. This study suggests that progressive AVB with normal QRS interval and accompanying DCM at later stages may represent a distinct type of DCM. The molecular mechanism by which the E82K mutation causes AVB as the prominent phenotype in DCM may be a focus of future studies.

Genetic mutation of familial dilated cardiomyopathy based on next‑generation semiconductor sequencing

“…At present, only three families with DCM resulting from similar mutations have been identified; the detection of the responsible mutation sites in the investigated family of the present study supports the hypothesis that p.E82K in LMNA may exhibit strong pathogenic effects that results in DCM ( 34 – 36 ). Additionally, studies with larger populations have not been conducted; however, functional studies in vitro have indicated a significant effect on protein function.…”

Lamin A/C mutations in dilated cardiomyopathy

“…Surprisingly, both Lmna H222P/+ and Lmna N195K/+ mice were found to have a phenotype and life expectancy similar to the wild-type [26,27]. Cells derived from both Lmna -/-and Lmna N195K/N195K mice were observed to have damaged and misshapen nuclei, showed increased fragility under mechanical strain and impaired gene transcription [27][28][29][30].…”

Cellular and Animal Models of Striated Muscle Laminopathies

“…Another model for DCM-CD is transgenic mice with cardiac-specific expression of the p.E82K lamin A/C variant ( Lmna E82K ) [115]. This variant results from an exon 1 LMNA mutation identified in a Chinese family with DCM-CD (atrioventricular block) [116,117]. Transgenics were comparable to their non-transgenic siblings at birth and at a young age [115].…”