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Am J Hum Genet. 2019 Dec 5;105(6):1237-1253. doi: 10.1016/j.ajhg.2019.11.002. Epub 2019 Nov 27.

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

Author information

1
Program in Developmental Biology, Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
2
Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
3
Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA.
4
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
5
Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Rady Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA.
8
Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, 11525, Saudi Arabia.
9
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 11525, Saudi Arabia.
10
Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, OK 26901, USA; Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
11
Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, OK 26901, USA; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
12
Assistance Publique des Hôpitaux de Paris, Unité de Génétique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire Paris, 75012, France; Département de Génétique et Embryologie Médicale, CRMR des Malformations et Maladies Congénitales du Cervelet, GRC ConCer-LD, Sorbonne Universités, Hôpital Trousseau, Paris, 75012 France.
13
Assistance Publique des Hôpitaux de Paris, Unité de Génétique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire Paris, 75012, France.
14
Assistance Publique des Hôpitaux de Paris, Service de Neuropédiatrie, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire Paris, 75012 France.
15
GeneDx, Inc., Gaithersburg, MD 20877, USA.
16
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97201, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97201, USA.
17
Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
18
Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada. Electronic address: p.campeau@umontreal.ca.

Abstract

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

KEYWORDS:

Drosophila; MiMIC; NCOA7; T2A-GAL4; TLDc; V-ATPase; mustard; oxidative stress; seizures; speech delay

PMID:
31785787
DOI:
10.1016/j.ajhg.2019.11.002

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