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

Abstract

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.

• Authors: Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H Seemann, Nicholas Stong, Peter G Kranz, Sujay Kansagra, Mohamad A Mikati, Joan Jasien, Mays El-Dairi, Paolo Galluzzi, Undiagnosed Diseases Network, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J Bellen
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 31 Issue 17 Pg. 2934-2950 (08 25 2022) ISSN: 1460-2083 [Electronic] England
• PMID: 35405010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• MicroRNAs
• DROSHA protein, human
• Ribonuclease III

Topics

• Epilepsy
• Humans
• Intellectual Disability (genetics)
• MicroRNAs (genetics, metabolism)
• Microcephaly (genetics)
• Nervous System Malformations
• Ribonuclease III (genetics, metabolism)