Figure 1.
Novel LMNA mutation (G232V) segregates with inherited cardiac conduction disease.
(A) Pedigree of the studied family. The pedigree shows the affection statuses, individual identifiers, and genotypes at LMNA c.G695T. The samples (marked by arrows) I-3, II-2, II-3, II-4 and III-1 were exome sequenced. The I-1, I-3 and II-1 samples were from healthy individuals, and the phenotype of sample III-1 was uncertain. (B) Sequencing result showing the heterozygous LMNA c.G695T (G232V) mutation. WT, wild type allele; MT, mutant allele. (C) Schematic of Lamin A protein. *G232V mutation in the 1B−2 linker region.
Figure 2.
Workflow and annotation pipeline for the identification of candidate variants.
(A) Workflow for finding candidate variants. (B) The number of SNV and Indel variants from GATK-called data sorted following the autosomal dominant model through the ANNOVAR pipeline. There were 52 SNV and 2 Indel variants remaining, and each variant was located in different genes.
Figure 3.
(A) The model of wild type LMNA (residues 81−383) was built using the HHblits-generated parameters from Modeller. (B) The G232V LMNA mutant model. (C) Higher magnification of (A). (D) Higher magnification of (B). G232 and V232 are shown as sticks. Modeling visualization was performed using PyMol (http://www.pymol.org).
Figure 4.
Expression of lamin A/C in cultured atrial cardiomyocytes.
HL-1 atrial cardiomyocytes transfected with wild-type lamin A (A) and lamin C (B) in fluorescent expression vectors, showing the cell nucleus with homogenous nuclear veil. HL-1 atrial cardiomyocytes transfected with p.G232V mutant lamin A (C) and lamin C (D), showing the cell nucleus with aggregates.