Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa

Hum Mol Genet. 2016 Apr 15;25(8):1479-88. doi: 10.1093/hmg/ddw022.

Mingchu Xu ¹, Takeyuki Yamada ², Zixi Sun ³, Aiden Eblimit ¹, Irma Lopez ⁴, Feng Wang ¹, Hiroshi Manya ², Shan Xu ¹, Li Zhao ⁵, Yumei Li ¹, Adva Kimchi ⁶, Dror Sharon ⁶, Ruifang Sui ³, Tamao Endo ², Robert K Koenekoop ⁴, Rui Chen ⁷

Affiliations

1 Department of Molecular and Human Genetics, Human Genome Sequencing Center.
2 Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
3 Department of Ophthalmology, Peking Union Medical College, Beijing 100730, China.
4 McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec H3H 1P3, Canada and.
5 Department of Molecular and Human Genetics, Human Genome Sequencing Center, Structural and Computational Biology and Molecular Biophysics Graduate Program.
6 Departments of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
7 Department of Molecular and Human Genetics, Human Genome Sequencing Center, Structural and Computational Biology and Molecular Biophysics Graduate Program, The Verna and Marrs Mclean Department of Biochemistry and Molecular Biology and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA, ruichen@bcm.edu.

PMID: 26908613 DOI: 10.1093/hmg/ddw022

Abstract

A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations in POMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages.

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