PLEC – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2Q

Plectin (PLEC; HGNC:9069) encodes a large cytolinker that maintains mechanical integrity in muscle. Autosomal recessive limb-girdle muscular dystrophy type 2Q (LGMD2Q; MONDO:0013390) is characterized by early-onset proximal muscle weakness without skin blistering, sometimes with ocular involvement.

Initial case report of two affected sisters identified compound heterozygous PLEC variants c.3064C>T (p.Gln1022Ter) in trans with c.11503G>A (p.Gly3835Ser) presenting with progressive limb-girdle weakness, ptosis, and ophthalmoparesis (PMID:25556389). A follow-up multi-patient study described two additional LGMD2Q patients harboring biallelic PLEC variants c.1379T>C (p.Val460Ala) and c.9007C>T (p.Arg3003Trp) among three families (PMID:38912134). A third independent report confirmed LGMD2Q in one patient with c.9940T>A (p.Phe3314Ile) and another missense allele, extending the phenotype (PMID:28447722).

Across these studies, five unrelated probands in three families exhibit autosomal recessive inheritance with compound heterozygous or homozygous loss-of-function and missense PLEC variants consistent with disease. The variant spectrum includes two premature stop codons (p.Gln1022Ter; p.Arg3003Trp) and three damaging missense changes (p.Val460Ala; p.Phe3314Ile; p.Gly3835Ser) across functional domains.

Muscle immunocytochemistry demonstrated markedly reduced plectin expression and mislocalization in patient biopsy specimens ([PMID:28447722]), supporting a loss-of-function mechanism. Isoform-specific plectin knockout mice develop dystrophic changes recapitulating human LGMD2Q, confirming functional concordance.

No conflicting reports dispute PLEC’s role in LGMD2Q. The genetic and experimental data together support a moderate clinical validity for PLEC in LGMD2Q.

Key Take-home: PLEC loss-of-function variants cause autosomal recessive LGMD2Q, and PLEC testing should be included in diagnostic panels for limb-girdle muscular dystrophy without skin involvement.

References

• Archives of Iranian Medicine • 2015 • Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy. PMID:25556389
• Unknown Journal • Unknown Year • Plectinopathy-associated disorders: three cases of LGMD2Q and EBS-MD PMID:38912134
• Molecular Medicine Reports • 2017 • Novel compound heterozygous PLEC mutations lead to early-onset limb-girdle muscular dystrophy PMID:28447722

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