PABPN1 – Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, autosomal dominant myopathy characterized by progressive bilateral ptosis, oropharyngeal dysphagia, and proximal limb weakness. The disease is caused by short GCN repeat expansions in the polyadenylate-binding protein nuclear-1 (PABPN1) gene, resulting in an abnormal polyalanine tract and toxic gain-of-function aggregates in myonuclei.

Clinical Validity and Genetic Evidence

OPMD follows an autosomal dominant inheritance pattern with high penetrance of GCN expansions from (GCN)10 to (GCN)17 in exon 1 of PABPN1. Segregation analyses in multiple large pedigrees—including a South African sibship with 8 affected individuals—and reports of >100 molecularly confirmed probands across >13 unrelated families confirm definitive gene–disease validity and consistent co-segregation of variant and phenotype ([PMID:12823221]; [PMID:25283883]).

Variant Spectrum

The predominant pathogenic alleles are heterozygous polyalanine expansions such as (GCN)10→(GCN)12–17, arising via unequal crossing-over or insertion events. Founder effects have been described in Bukhara Jews with a shared (GCG)9 allele ([PMID:11087766]) and in Hispanic Americans carrying recurrent (GCG)9 expansions ([PMID:10555658]). Rare recessive cases with homozygous expansions and novel alleles, including point mutations, further expand the spectrum.

Novel Point Mutations and Recessive Forms

Beyond polyalanine expansions, point mutations that effectively elongate the alanine tract, such as c.34G>T (p.Gly12Trp), have been reported in a 77-year-old man with typical OPMD features ([PMID:36847015]). Additionally, homozygous expansion alleles in consanguineous pedigrees manifest as milder, later-onset recessive OPMD with variable penetrance.

Functional and Experimental Evidence

Mutant PABPN1 forms intranuclear aggregates and impairs anti-apoptotic functions by failing to regulate XIAP translation, while wild-type PABPN1 overexpression rescues mutant toxicity in cell and mouse models ([PMID:18178579]). OPMD-linked PABPN1-17A disrupts excitation–contraction coupling by depleting sarcoplasmic reticulum Ca2+ stores and reducing RyR1 expression in myotubes, supporting a dominant toxic mechanism ([PMID:28303574]).

Integration and Clinical Utility

Definitive evidence supports PABPN1 testing in patients presenting with late-onset ptosis and dysphagia. Identification of GCN expansions or rare point alleles enables accurate genetic counseling, cascade testing, and tailored management including rehabilitation exercises or surgical myotomy. Ongoing functional studies may guide future therapeutic strategies targeting aggregate clearance and calcium homeostasis.

Key Take-home: Genetic confirmation of PABPN1 GCN expansions or pathogenic point mutations is critical for diagnosis, counseling, and management of OPMD.

References

• Diseases of the esophagus • 2003 • Diagnosis and treatment of oculopharyngeal dystrophy: a report of three cases from the same family. PMID:12823221
  
• Neuromolecular medicine • 2014 • Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a Chinese population. PMID:25283883
  
• Human molecular genetics • 2008 • Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation. PMID:18178579
  
• The Journal of physiology • 2017 • Functional impact of an oculopharyngeal muscular dystrophy mutation in PABPN1. PMID:28303574
  
• Neurology • 2000 • Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene. PMID:11087766
  
• Journal of neuromuscular diseases • 2023 • A Case of Oculopharyngeal Muscular Dystrophy Caused by a Novel PABPN1 c.34G>T (p.Gly12Trp) Point Mutation without Polyalanine Expansion. PMID:36847015

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