View Program - 63rd Annual Drosophila Research Conference

N-glycanase 1 (NGLY1) deficiency is a rare disease caused by autosomal recessive loss of function mutations in the NGLY1 gene and is the only known congenital disorder of deglycosylation. Patients suffer from movement disorder, developmental delay, liver dysfunction, and alacrima. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded glycoproteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, NGLY1’s physiological significance in ERAD is not understood. One way to understand disease pathogenesis is to investigate the effects of genetic variation and modifier genes on disease presentation. Our lab created a Drosophila model of NGLY1 deficiency that faithfully recapitulates several disease phenotypes observed in patients, including movement disorder, seizures, and lethality. We crossed this Drosophila model of NGLY1 deficiency with the Drosophila Genetics Reference Panel (DGRP), a collection of ~200 inbred fly strains with fully sequenced genomes, and scored for proportion of NGLY1 knockdown flies surviving to adulthood. The genetic variation of the DGRP led to a spectrum of lethality ranging from strains that had 100% lethality to 100% viability. A genome wide association study (GWAS) generated a list of 61 candidate modifier genes of NGLY1 deficiency. Nine of these candidate genes encode ER resident proteins, proteins with known ERAD functions, or are involved with protein homeostasis. CG31690 and CG4341 were two independent unlinked hits in the GWAS that are orthologs of a single human gene, TMTC2, which encodes an ER adaptor protein involved with calcium homeostasis. Hrd3 and CG8405, orthologs of SEL1L and TMEM259, were both hits and are known components of ERAD complexes that retrotranslocate misfolded proteins from the ER to the cytoplasm for degradation. We are functionally characterizing several of these candidate modifier genes of NGLY1 deficiency using Drosophila and cell culture models. The study of modifier genes can provide new insights into the etiology of the disease and functions of NGLY1, laying the foundation for the development of personalized therapeutics.

Genetic modifiers of NGLY1 deficiency identified through a Drosophila genetic screen point to the role of NGLY1 in ERAD

**Genetic modifiers of NGLY1 deficiency identified through a Drosophila genetic screen point to the role of NGLY1 in ERAD**