Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum–associated degradation pathway

Abstract

Purpose The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction. Methods Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. Results All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. Conclusions NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.

Novel genetic causes for cerebral visual impairment

“…Previously, CVI has been reported as part of congenital disorders of glycosylation (CDG) type 1a (PMM2), type 1q (SRD5A3), and type 1v (NGLY1). 8,28,30,31 The phenotype of patient 2 with NGLY1 variants is similar to the previously reported patients, including the microcephaly, hypotonia, movement disorder, and alacrima. 28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing.…”

“…13,[27][28][29] For five genes, HSPG2, PHKB, SRP72, SYNE1, and TENM3, the reported phenotype in literature was not in line with the phenotype of the patient, and those variants were classified as unlikely to be causative for CVI in those patients (#224410, #255800, #261750, #614675, #612998, #610743, #615145). In APOPT1, the phenotype was also not in line with the reported phenotype (#220110).…”

The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated

“…Two new developments in genetics promise to dramatically shorten the time to reach a successful diagnosis: next-generation sequencing (NGS) and family engagement through social media. The very speed with which Need et al 2 and Enns et al 1 were published suggests a new model for clinicians and researchers. In this model, families, patients, and scientists work jointly to find new patients, confirm or refute hypotheses, exchange clinical information, enhance collaboration methods, and support research toward understanding and treatment.…”

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We are the fathers of two patients with a newly diagnosed syndrome that is highlighted in the study by Enns et al 1 Our children are two among a handful of others in the world with this disease caused by mutations in the NGLY1 gene. It is the first recognized disorder of deglycosylation.

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Cerebral visual impairment and intellectual disability caused by PGAP1 variants

“…6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells.…”