The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.

Journal Article (Journal Article)

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.

Full Text

Duke Authors

Cited Authors

  • Barish, S; Senturk, M; Schoch, K; Minogue, AL; Lopergolo, D; Fallerini, C; Harland, J; Seemann, JH; Stong, N; Kranz, PG; Kansagra, S; Mikati, MA; Jasien, J; El-Dairi, M; Galluzzi, P; Undiagnosed Diseases Network, ; Ariani, F; Renieri, A; Mari, F; Wangler, MF; Arur, S; Jiang, Y-H; Yamamoto, S; Shashi, V; Bellen, HJ

Published Date

  • August 25, 2022

Published In

Volume / Issue

  • 31 / 17

Start / End Page

  • 2934 - 2950

PubMed ID

  • 35405010

Pubmed Central ID

  • PMC9433733

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddac085


  • eng

Conference Location

  • England