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

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rare Diseases

Background:

• Plectinopathies are rare genetic neuromuscular disorders resulting from mutations in the PLEC gene, which encodes the cytoskeletal protein plectin.
• Plectin plays a crucial role in maintaining cellular structure by linking cytoskeletal components across various tissues.

Observation:

• This study details a clinical case of a 26-year-old patient with limb-girdle muscle dystrophy type 2Q, an early-onset plectinopathy variant.
• Histopathological and ultrastructural analyses of muscle biopsies revealed plectin loss, cytoskeleton disorganization, and incomplete rhabdomyogenesis.
• The patient exhibited progressive limb-girdle muscle weakness, axial muscle atrophy, muscle hypertrophy in specific groups, and intermittent dyspnea, with no skin manifestations.

Findings:

• A novel homozygous likely pathogenic variant (NM_201378.3:c.58G>T) in the PLEC gene's isoform 1f was identified as the cause of the patient's condition.
• This represents the third reported case of limb-girdle muscle dystrophy type 2Q with an isolated myodystrophic phenotype linked to a PLEC 1f isoform variant.
• Severe lung injury, including non-infectious bronchiolitis and atelectasis, was observed in the patient and his siblings with the same phenotype.

Implications:

• The findings expand the understanding of PLEC gene variants and their association with limb-girdle muscle dystrophy type 2Q.
• This research suggests a potential role for plectin deficiency in the pathogenesis of severe lung injury observed in affected individuals.
• Further investigation into plectin's function in lung tissue is warranted to explore therapeutic strategies for these rare conditions.