Further evidence for POMK as candidate gene for WWS with meningoencephalocele
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(2020) 15:242
RESEARCH
Open Access
Further evidence for POMK as candidate gene for WWS with meningoencephalocele Luisa Paul1 , Katrin Rupprich1, Adela Della Marina1, Anja Stein2, Magdeldin Elgizouli3, Frank J. Kaiser3, Bernd Schweiger4, Angela Köninger5, Antonella Iannaccone5, Ute Hehr6, Heike Kölbel1, Andreas Roos1,7, Ulrike Schara-Schmidt1 and Alma Kuechler3*
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 (alphadystroglycanopathy). 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. Keywords: POMK, Protein O-mannose kinase, Walker-Warburg syndrome, Alpha-dystroglycanopathy, Congenital muscular dystrophy, Meningoencephalocele
Background Encephalocele is a congenital malformation in which herniated meninges (with or without brain tissue) protrude outside the skull. The underlying cause has still not been completely elucidated [1]. Encephalocele is characteristic for some syndromal diseases, such as Knobloch syndrome (COL18A1), as well as certain * Correspondence: [email protected] 3 Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany Full list of author information is available at the end of the article
ciliopathies such as Meckel-Gruber and Joubert syndromes, and several chromosomal aberrations [2]. Regarding diseases affecting proper glycosylation of alphadystroglycan, the manifestation of a meningoencephalocele has only rarely been associated with defects in known genes such as POMT1 and ISPD [3, 4]. Geis and colleagues discussed the presence of an encephalocele as possibly an indicator of the presence of pathogenic POMT1 mutations in terms of a phenotype-genotype correlation [3].
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