Glu20Ter Variant in PLEC 1f Isoform Causes Limb-Girdle Muscle Dystrophy with Lung Injury

Abstract

Plectinopathies are orphan diseases caused by PLEC gene mutations. PLEC is encoding the protein plectin, playing a role in linking cytoskeleton components in various tissues. In this study, we describe the clinical case of a 26-year-old patient with an early onset plectinopathy variant “limb-girdle muscle dystrophy type 2Q,” report histopathological and ultrastructural findings in m. vastus lateralis biopsy and a novel homozygous likely pathogenic variant (NM_201378.3:c.58G>T, NP_958780.1:p.Glu20Ter) in isoform 1f of the gene PLEC. The patient had an early childhood onset with retarded physical development, moderate weakness in pelvic girdle muscles, progressive weakening of limb-girdle muscles after the age of 21, pronounced atrophy of axial muscles, and hypertrophy of the gastrocnemius, deltoid, and triceps muscles, intermittent dyspnea, and no skin involvement. Findings included: non-infectious bronchiolitis and atelectasis signs, biopsy revealed myodystrophal pattern without macrophage infiltration, muscle fiber cytoskeleton disorganization resulted from the plectin loss, incomplete reparative rhabdomyogenesis, and moderate endomysial fibrosis. We have determined a novel likely pathogenic variant in PLEC 1f isoform that causes limb-girdle muscle dystrophy type 2Q and described the third case concerning an isolated myodystrophic phenotype of LGMD2Q with the likely pathogenic variant in PLEC 1f isoform. In addition, we have demonstrated the presence of severe lung injury in a patient and his siblings with the same myodystrophic phenotype and discussed the possible role of plectin deficiency in its pathogenesis.

Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

“…This 9 bp deletion contains the ATG initiation codon located in exon 1f, and results in impaired translation of the plectin 1f isoform exclusively [ 10 ]. More recently, another truncating variant in exon 1f (p.Glu20Ter), also resulting in a LGMD R17 phenotype, has been reported [ 20 ].…”

Novel autophagic vacuolar myopathies: Phenotype and genotype features

“…We are uncertain about the mutation that causes this trait. Respiratory involvement has been described in only one adult GSDIII patient following strict fasting [58], and in one patient with a PLEC mutation who had an early childhood onset [30]. Conversely, it occurs in both sporadic and familial cases of titinopathies, with onset in adulthood [59,60].…”

“…The Plectin (PLEC) gene is related to a wide spectrum of clinical phenotypes, including limb-girdle muscular dystrophy (LGMD) type 2Q associated with respiratory pathology [30]. PLEC mutations have been found in three unrelated myopathic patients, whose muscle biopsies were described to have rimmed and no rimmed vacuoles in one patient, autophagic vacuoles in the other two [31,32].…”

“…Respiratory involvement has been described in only one adult GSDIII patient following strict fasting [58], and in one patient with a PLEC mutation who had an early childhood onset [30].…”

Identifying Plectin Isoform Functions through Animal Models

“…The second mutation identified in exon 1f, c.58G > T, p.Glu20X (reference sequence NM_201378.3), caused LGMDR17. The affected individuals, three siblings, presented muscular dystrophy aggravated by respiratory problems, mainly atelectasis and dyspnea; two of the siblings died because of lung collapse [ 107 ]. As the reported lung phenotype had never been diagnosed in plectin-deficient patients or mice, although plectin is prominently expressed in alveolar epithelial cells [ 108 ], it seems that neither the patients nor the mice were thoroughly examined for pulmonary defects.…”