• neurodegenerative disease

In Drosophila, a loss-of-function mutation of Dmel\Nrd1 was recovered in a genetic screen for mutations causing neurodegeneration in photoreceptor neurons. It was subsequently determined that a frameshift mutation in the orthologous human NRDC gene is a top candidate for implication in a syndrome of severe global developmental delay and ataxia; it appears to exhibit autosomal recessive inheritance. NRDC encodes nardilysin convertase, a zinc-dependent endopeptidase. For the orthologous Dmel\Nrd1, classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. A second gene in Drosophila, CG10588, is also orthologous to human NRDC.

Multiple UAS alleles of the human Hsap\NRDC gene have been introduced into flies, including wild-type and a variant implicated in human disease. See the 'Disease-Implicated Variants' table below. Heterologous rescue (functional complementation) is observed: ubiquitous expression of the wild-type human gene rescues the lethality and the neurophysiology defects of Nrd1 loss-of-function mutations.

Animals homozygous for loss-of-function mutations of Dmel\Nrd1 die during the pupal stage; somatic clones in the adult eye show age-progressive loss of synaptic transmission in photoreceptor cells. Physical and genetic interactions have been described for Nrd1; see below and in the Nrd1 gene report.

Work in Drosophila has contributed to the characterization of NRDC as a mitochondrial chaperone or co-chaperone for OGDH/OGHDL; see the human disease model reports 'neurodegenerative disease, OGDHL-related' (FBhh0000719) and 'oxoglutarate dehydrogenase deficiency' (FBhh0001423).

[updated Jan. 2022 by FlyBase; FBrf0222196]