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

Publication ,  Journal Article
Barish, S; Senturk, M; Schoch, K; Minogue, AL; Lopergolo, D; Fallerini, C; Harland, J; Seemann, JH; Stong, N; Kranz, PG; Kansagra, S; Mari, F ...
Published in: Hum Mol Genet
August 25, 2022

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.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 25, 2022

Volume

31

Issue

17

Start / End Page

2934 / 2950

Location

England

Related Subject Headings

  • Ribonuclease III
  • Nervous System Malformations
  • Microcephaly
  • MicroRNAs
  • Intellectual Disability
  • Humans
  • Genetics & Heredity
  • Epilepsy
  • 3105 Genetics
  • 11 Medical and Health Sciences
 

Citation

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Barish, S., Senturk, M., Schoch, K., Minogue, A. L., Lopergolo, D., Fallerini, C., … Bellen, H. J. (2022). The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder. Hum Mol Genet, 31(17), 2934–2950. https://doi.org/10.1093/hmg/ddac085
Barish, Scott, Mumine Senturk, Kelly Schoch, Amanda L. Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, et al. “The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.Hum Mol Genet 31, no. 17 (August 25, 2022): 2934–50. https://doi.org/10.1093/hmg/ddac085.
Barish S, Senturk M, Schoch K, Minogue AL, Lopergolo D, Fallerini C, et al. The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder. Hum Mol Genet. 2022 Aug 25;31(17):2934–50.
Barish, Scott, et al. “The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.Hum Mol Genet, vol. 31, no. 17, Aug. 2022, pp. 2934–50. Pubmed, doi:10.1093/hmg/ddac085.
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. The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder. Hum Mol Genet. 2022 Aug 25;31(17):2934–2950.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

August 25, 2022

Volume

31

Issue

17

Start / End Page

2934 / 2950

Location

England

Related Subject Headings

  • Ribonuclease III
  • Nervous System Malformations
  • Microcephaly
  • MicroRNAs
  • Intellectual Disability
  • Humans
  • Genetics & Heredity
  • Epilepsy
  • 3105 Genetics
  • 11 Medical and Health Sciences