NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy

Abstract

N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson's disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.

Keywords: Deglycosylation; Intellectual disability; NGLY1; Neuromotor defect; Whole-exome sequencing.

Figure 1

A) Pedigree of Family NG1278: Pedigree of family NG1278 demonstrating the affected siblings. Note the consanguinity of the parents. B) Sural Nerve Biopsy of Patient NG1278-1: 40× magnification image of a representative section of sural nerve tissue obtained via biopsy from patient NG1278-1. There is general axonal loss and decreased myelination; # indicates the marked decrease in small myelinated fibers; * indicates the segmentally decreased number of large diameter myelinated fibers; non-myelinated fibers also demonstrate a slight decrease in numbers, but appear relatively spared (arrow). C) Brain MRI of Patient NG1278-1: Sagittal T1 weighted brain MRI demonstrating a thin spinal cord. No cortical abnormalities were noted. D) Sequence Alignment: Whole-exome sequencing results for patient NG1278-1 demonstrating the homozygous 4 base pair deletion in NGLY1 – delTTGA. The top line represents the wild-type reference sequence. The subsequent lines below the reference lines depict the results from exome sequencing. Each line represents a distinct coverage read. Coverage achieved for this region was 15×. E) Sanger Sequencing Results: Chromatographs obtained via Sanger sequencing analysis of the two patients and their parents. Sanger sequencing of wild-type control DNA was also performed. Note that the mutation identified via whole-exome sequencing was confirmed as being homozygous versus heterozygous, in the two affected siblings versus their parents, respectively. The bases outlined in red in the wild-type sequence indicate the mutated base pairs. F) Schematic Representation of N-glycanase 1: Figure shows the functional and conserved domains. Arrow head indicates location of the identified mutation. G) CNV Analysis of NG1278-1: The log ratio comparing NG1278-1 and control sequence depths of coverage for each exon are depicted as gray dots. The black lines demonstrate regions of segmented copy neutral events, green lines are segmented deletion events and red lines are amplification events.