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

Barish, Scott

Senturk, Mumine

Schoch, Kelly

Minogue, Amanda L

Lopergolo, Diego

Fallerini, Chiara

Harland, Jake

Seemann, Jacob H

Stong, Nicholas

Kranz, Peter G

Kansagra, Sujay

Mikati, Mohamad A

Jasien, Joan

El-Dairi, Mays

Galluzzi, Paolo

Undiagnosed Diseases Network

Ariani, Francesca

Renieri, Alessandra

Mari, Francesca

Wangler, Michael F

Arur, Swathi

Jiang, Yong-Hui

Yamamoto, Shinya

Shashi, Vandana

Bellen, Hugo J

2022-09-01T16:12:58Z

2022-09-01T16:12:58Z

2022-04-11

2022-09-01T16:12:58Z

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.

6566430

0964-6906

1460-2083

https://hdl.handle.net/10161/25647

eng

Oxford University Press (OUP)

Human molecular genetics

10.1093/hmg/ddac085

Undiagnosed Diseases Network

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

Journal article

Mikati, Mohamad A|0000-0003-0363-8715

El-Dairi, Mays|0000-0002-4365-9038

ddac085

Duke

School of Medicine

Basic Science Departments

Clinical Science Departments

Institutes and Centers

Neurobiology

Pediatrics

Pediatrics, Neurology

Institutes and Provost's Academic Units

University Institutes and Centers

Duke Institute for Brain Sciences

Duke-UNC Center for Brain Imaging and Analysis

Initiatives

Duke Science & Society

Published