POMT1 – Muscle-eye-brain Disease

POMT1 encodes protein O-mannosyltransferase 1, essential for α-dystroglycan glycosylation. Biallelic POMT1 variants underlie autosomal recessive muscle-eye-brain disease (MEB), a dystroglycanopathy characterized by congenital muscular dystrophy, ocular defects, and neuronal migration abnormalities.

Autosomal recessive inheritance is supported by segregation of POMT1 variants in multiple families: 13 affected relatives in 5 independent kindreds show concordant biallelic variant transmission, consistent with AR segregation (PMID:31311558).

In a fetal type II lissencephaly series (47 fetuses from 41 unrelated families), POMT1 involvement was demonstrated in 32% of cases, accounting for approximately 15 probands with severe MEB-like phenotypes and pregnancy terminations (PMID:17559086).

A postnatal cohort of 35 patients (27 families) with POMT1-related dystroglycanopathies included one MEB case and delineated a genotype–phenotype correlation: null mutations led to severe Walker–Warburg syndrome or MEB, whereas at least one missense allele yielded milder limb-girdle muscular dystrophy (PMID:31311558).

The variant spectrum encompasses at least nine distinct POMT1 mutations: three missense (e.g., c.598G>C (p.Ala200Pro)), five protein-truncating (nonsense/frameshift), and one canonical splice-site alteration (c.1698+1G>A) identified across MEB and related phenotypes.

Functional assays demonstrate that patient-derived POMT1 mutations abolish O-mannosyltransferase activity when co-expressed with POMT2 in Sf9 cells, confirming a loss-of-function mechanism (PMID:15522202).

Integration of robust genetic and experimental data supports a Strong clinical validity classification for POMT1 in MEB. Early POMT1 testing facilitates definitive diagnosis, genetic counseling, and management of AR dystroglycanopathies.

References

• Human mutation | 2007 | Molecular heterogeneity in fetal forms of type II lissencephaly. PMID:17559086
• Orphanet journal of rare diseases | 2019 | Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. PMID:31311558
• Biochemical and biophysical research communications | 2004 | Mutations of the POMT1 gene found in patients with Walker-Warburg syndrome lead to a defect of protein O-mannosylation. PMID:15522202

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