A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block

Abstract

Background: LMNA/C mutations have been linked to the premature aging syndrome Hutchinson's progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype-phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.

Results: DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members. In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype-phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.

Conclusions: Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.

Keywords: Arrhythmia; Atrioventricular block; Dilated cardiomyopathy; Exome sequencing; Lamin A/C.

Figure 1

Pedigree of the studied atrioventricular block family. Generation is indicated with roman numerals, and individual ID is indicated with Arabic numerals. Solid squares (males) and circles (females) indicate affected subjects, open symbols indicate unaffected subjects, and gray symbols indicate unknown disease status. Diamonds indicate not-relevant subjects, and the numbers within them are the number of subjects. Diagonal lines indicate dead subjects. Arrows identify the analyzed subjects. M indicates the subjects carrying rs56816490. PM indicates pacemaker implantation. The proband is indicated with a red oval. Ages of subject are given beneath the individual’s ID number.

Figure 2

Electropherogram of the lamin A/C gene. Electropherograms of control (upper) and atrioventricular block-affected (lower) subjects showing heterozygosity for the LMNA/C mutation G613A in the latter. Heterozygosity is indicated by the presence of two peaks corresponding to G and A (arrow and magnification).

Figure 3

Frequency analysis of controls with PCR for rs56816490. Image of electrophoretic analysis of PCR validation amplifications of genomic DNA from pedigree subjects (III:2 and IV:4) and independent controls. Amplification of the mutated allele of LMNA/C (G613A) is present only in the affected subject (IV:4, the proband).