Mutation update: The spectra of PLEC sequence variants and related plectinopathies

Abstract

Plectin, encoded by PLEC, is a cytoskeletal linker of intermediate filaments expressed in many cell types. Plectin consists of three main domains that determine its functionality: the N-terminal domain, the Rod domain, and the C-terminal domain.Molecular defects of PLEC correlating with the functional aspects lead to a group of rare heritable disorders, plectinopathies. These multisystem disorders include an autosomal dominant form of epidermolysis bullosa simplex (EBS-Ogna), limb-girdle muscular dystrophy (LGMD), aplasia cutis congenita (ACC), and an autosomal recessive form of EBS, which may associate with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and/or congenital myasthenic syndrome (EBS-MyS). In this study, genotyping of over 600 Iranian patients with epidermolysis bullosa by nextgeneration sequencing identified 15 patients with disease-causing PLEC variants. This mutation update analyzes the clinical spectrum of PLEC in our cohort and in the literature and demonstrates the relationship between PLEC genotype and phenotypic manifestations. This study has integrated our seven novel PLEC variants and phenotypic findings with previously published data totaling 116 variants to provide the most complete overview of pathogenic PLEC variants and related disorders.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…PLEC -CMS has been reported in 22 patients since 1999 [ 53 , 274 , 332 , 334 , 336 , 337 , 338 , 339 ]. Although LGMD17 and CMS are always present, EBS may [ 332 , 334 , 336 , 338 ] or may not [ 53 , 337 ] be present.…”

“…Some patients also show mild EBS [ 338 ]. A review of 117 PLEC -EBS patients carrying pathogenic variants in PELC showed that 14 patients also had CMS [ 339 ]. However, the authors observed the presence of CMS in 7 out of 15 patients in their own cohort of PLEC -EBS [ 339 ], indicating that CMS was likely to be underdiagnosed and that the prevalence of CMS was higher than reported.…”

Molecular‐based phenotype variations in amelogenesis imperfecta

“…EB is mainly divided into four types: simplex, junctional, dystrophic, and Kindler, and each type has its own subtypes (Fine et al, 2014; Has et al, 2020; Intong & Murrell, 2012). The enamel abnormalities could be found in dystrophic, junctional, and simplex types of EB (Argyropoulou et al, 2018; Vahidnezhad et al, 2022).…”

“…SEB‐MD is caused by mutations in the PLEC gene (OMIM *601282), which encodes plectin, a structural protein expressed in several tissues such as epithelia and muscle. SEB mainly causes enamel hypoplasia (Argyropoulou et al, 2018; Vahidnezhad et al, 2022).…”

Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain

“…Genetic variants in human Plec have been reported to be associated with a number of Plectin -associated diseases (plectinopathies), including autosomal recessive generalized intermediate epidermolysis bullosa simplex 5D (EBS5D; MIM 601487), autosomal dominant epidermolysis bullosa simplex 5A, Ogna type (EBS5A; MIM 131950), autosomal recessive epidermolysis bullosa simplex 5B with muscular dystrophy (EBS5B; MIM 226670), autosomal recessive epidermolysis bullosa simplex with pyrolic atresia (EBSPA; MIM 612138), and autosomal recessive limb-girdle muscular dystrophy-17 (LGMDR17; MIM 613723) [ 9 , 10 , 11 ]. In the majority of cases, the underlying genetic changes in these conditions are truncating or indel variants in one or both alleles.…”