Mutation in Exon 1f of PLEC, Leading to Disruption of Plectin Isoform 1f, Causes Autosomal-Recessive Limb-Girdle Muscular Dystrophy

Abstract

Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of inherited muscular disorders manifesting symmetric, proximal, and slowly progressive muscle weakness. Using Affymetrix 250K SNP Array genotyping and homozygosity mapping, we mapped an autosomal-recessive LGMD phenotype to the telomeric portion of chromosome 8q in a consanguineous Turkish family with three affected individuals. DNA sequence analysis of PLEC identified a homozygous c.1_9del mutation containing an initiation codon in exon 1f, which is an isoform-specific sequence of plectin isoform 1f. The same homozygous mutation was also detected in two additional families during the analysis of 72 independent LGMD2-affected families. Moreover, we showed that the expression of PLEC was reduced in the patient's muscle and that there was almost no expression for plectin 1f mRNA as a result of the mutation. In addition to dystrophic changes in muscle, ultrastructural alterations, such as membrane duplications, an enlarged space between the membrane and sarcomere, and misalignment of Z-disks, were observed by transmission electron microscopy. Unlike the control skeletal muscle, no sarcolemmal staining of plectin was detected in the patient's muscle. We conclude that as a result of plectin 1f deficiency, the linkage between the sarcolemma and sarcomere is broken, which could affect the structural organization of the myofiber. Our data show that one of the isoforms of plectin plays a key role in skeletal muscle function and that disruption of the plectin 1f can cause the LGMD2 phenotype without any dermatologic component as was previously reported with mutations in constant exons of PLEC.

Networking and anchoring through plectin: a key to IF functionality and mechanotransduction

“…A dominant missense mutation causes EBS-Ogna and affects only the skin [21,68]. A homozygous recessive mutation in exon 1f results in Limb-girdle muscular dystrophy without EBS [49].…”

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

“…1A) was performed using the Affymetrix GeneChip Human Mapping 250K NspI Array. Genotype files (.chp) generated using Affymetrix GTYPE software were analysed via VIGENOS (Visual Genome Studio) software (Hemosoft, Ankara) [16]. Genome-wide haplotypes were constructed according to data obtained from the index case (IV:5).…”

Functional and Genetic Analysis of Plectin in Skin and Muscle

“…Others include EBS-MD combined with myasthenic syndrome, EBS with pyloric atresia (OMIM #612138), and EBS-Ogna (OMIM #131950). Distinct and specific disease phenotypes have been expected for mutations in the alternative first exons, and recently such mutations have been identified in patients: a homozygous 9 bp deletion in exon 1f (encoding an important muscle isoform) leading to limb-girdle MD type 2Q (LGMD2Q, OMIM #613723) without skin involvement (Gundesli et al, 2010) and a homozygous nonsense mutation in exon 1a (predominantly expressed in keratinocytes) causing EBS without extracutaneous involvement (Gosty nska et al, 2015).…”