Further evidence for POMK as candidate gene for WWS with meningoencephalocele

Abstract

Background Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition. Results Here, we report on male monozygotic twins with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Both twins were found to harbor a homozygous nonsense mutation c.640C>T, p.214* in POMK, confirming the clinical diagnosis and supporting the concept that POMK mutations can be causative of WWS. Conclusion Our combined data suggest a more important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families; only five showed the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. We expand the phenotypic and mutational spectrum of POMK-associated WWS and provide evidence of the broad phenotypic variability of POMK-associated disease.

Regulation of secretory pathway kinase or kinase-like proteins in human cancers

“…O-mannosylation is effective on the Ser and Thr side chains to improve protein stability and solubility ( 32 ). POMK (protein-O-mannose kinase) encodes protein-O-mannose kinase, which is essential in extracellular matrix composition and involved in the proper glycosylation and function of the dystroglycan complex ( 33 , 34 ).…”

“…Mutations of POMK lead to a spectrum of congenital disorders of glycosylation and limb-girdle muscular dystrophies by influencing the biosynthesis of functional alpha-dystroglycan ( 33 , 164 – 167 ). POMK mutations cause not only Walker–Warburg syndrome ( 34 ) but also a more severe subtype, type C12 (MDDGC12) limb-girdle muscular dystrophy-dystroglycanopathy and type A12 (MDDGA12) congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies ( 164 , 165 , 168 , 169 ). POMK interaction proteins are strongly enriched in membrane proteins and metabolic pathways, demonstrating an important role in developmental and metabolic disorders ( 167 ).…”

Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families

“…In one of the WWS cases (S1), we identified a missense variant in POMK , which is a very rare cause of dystroglycanopathy. To date, only nine pathogenic POMK variants have been reported worldwide in 16 cases, and five of them were stillbirth or fetuses from induced termination of pregnancy [ 46 ]. Six out of nine variants cause WWS while the remaining three cause limb-girdle muscular dystrophy [ 46 ].…”

“…To date, only nine pathogenic POMK variants have been reported worldwide in 16 cases, and five of them were stillbirth or fetuses from induced termination of pregnancy [ 46 ]. Six out of nine variants cause WWS while the remaining three cause limb-girdle muscular dystrophy [ 46 ]. POMK genotype/phenotype correlations are complex because even variants leading to expression of a significantly truncated protein can result in a mild phenotype [ 47 ].…”