MYPN – Cap Myopathy

Autosomal recessive MYPN mutations underlie cap myopathy, a congenital skeletal muscle disorder marked by hanging big toe and Z-line cap features. MYPN (Gene Symbol) encodes myopalladin, a sarcomeric protein that anchors nebulin and nebulette to α-actinin at the Z line. While autosomal dominant alleles of MYPN cause various cardiomyopathies, recessive alleles produce skeletal myopathies including cap and nemaline subtypes. The cap myopathy phenotype expands the clinical spectrum of MYPN deficiency.

To date, eight affected individuals from seven unrelated families have been reported with autosomal recessive cap myopathy (PMID:31133047). In the latest consanguineous pedigree, two siblings presented with congenital to adult-onset muscle weakness, hanging big toe, and progressive spine and hand contractures. Muscle biopsies showed minimal changes with internal nuclei and type 1 fiber predominance, without classical nemaline rods or cap structures but with consistent Z-line fragmentation. Cardiac imaging in these patients revealed late gadolinium enhancement, indicating subclinical cardiac involvement.

Whole exome sequencing identified a homozygous loss-of-function single-nucleotide deletion in exon 11 of MYPN in both siblings (PMID:31133047). This frameshift abolishes full-length myopalladin expression on immunoblot and disrupts Z-line localization by immunofluorescence. Segregation analysis confirmed co-segregation of the variant with disease in the two affected siblings. No unaffected family members carried the homozygous allele.

Functional studies demonstrate that absence of myopalladin leads to ultrastructural Z-line defects mirroring human pathology, consistent with a loss-of-function mechanism. These findings concord with earlier reports of recessive MYPN variants causing cap and nemaline myopathies with overlapping ultrastructural alterations. No studies have refuted the MYPN–cap myopathy association or implicated alternative genes in this phenotype.

In summary, autosomal recessive loss-of-function variants in MYPN cause cap myopathy with characteristic clinical and ultrastructural features. This body of evidence supports a moderate level of clinical validity for the MYPN–cap myopathy association, guiding molecular diagnosis and counselling. MYPN sequencing should be considered in patients presenting with congenital myopathy, hanging big toe, and Z-line fragmentation.

References

• Skeletal muscle • 2019 • Congenital myopathy with hanging big toe due to homozygous myopalladin (MYPN) mutation. PMID:31133047

Evidence Based Scoring (AI generated)