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

Julia Wang, Justine Rousseau, Emily Kim, Sophie Ehresmann, Yi Ting Cheng, Lita Duraine, Zhongyuan Zuo, Ye Jin Park, David Li-Kroeger, Weimin Bi, Lee Jun Wong, Jill Rosenfeld, Joseph Gleeson, Eissa Faqeih, Fowzan S. Alkuraya, Klaas J. Wierenga, Jiani Chen, Alexandra Afenjar, Caroline Nava, Diane DoummarBoris Keren, Jane Juusola, Markus Grompe, Hugo J. Bellen, Philippe M. Campeau

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1237-1253
Number of pages17
JournalAmerican Journal of Human Genetics
Volume105
Issue number6
DOIs
StatePublished - Dec 5 2019

Fingerprint

Cerebellar Diseases
Mustard Plant
Atrophy
Language Development Disorders
Loss of Heterozygosity
Diptera
Intellectual Disability
Drosophila
Seizures
Oxidative Stress
Complementary DNA
Fibroblasts
Phenotype
Neurons
Mutation
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. / Wang, Julia; Rousseau, Justine; Kim, Emily; Ehresmann, Sophie; Cheng, Yi Ting; Duraine, Lita; Zuo, Zhongyuan; Park, Ye Jin; Li-Kroeger, David; Bi, Weimin; Wong, Lee Jun; Rosenfeld, Jill; Gleeson, Joseph; Faqeih, Eissa; Alkuraya, Fowzan S.; Wierenga, Klaas J.; Chen, Jiani; Afenjar, Alexandra; Nava, Caroline; Doummar, Diane; Keren, Boris; Juusola, Jane; Grompe, Markus; Bellen, Hugo J.; Campeau, Philippe M.

In: American Journal of Human Genetics, Vol. 105, No. 6, 05.12.2019, p. 1237-1253.

Research output: Contribution to journalArticle

Wang, J, Rousseau, J, Kim, E, Ehresmann, S, Cheng, YT, Duraine, L, Zuo, Z, Park, YJ, Li-Kroeger, D, Bi, W, Wong, LJ, Rosenfeld, J, Gleeson, J, Faqeih, E, Alkuraya, FS, Wierenga, KJ, Chen, J, Afenjar, A, Nava, C, Doummar, D, Keren, B, Juusola, J, Grompe, M, Bellen, HJ & Campeau, PM 2019, 'Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction', American Journal of Human Genetics, vol. 105, no. 6, pp. 1237-1253. https://doi.org/10.1016/j.ajhg.2019.11.002
Wang, Julia ; Rousseau, Justine ; Kim, Emily ; Ehresmann, Sophie ; Cheng, Yi Ting ; Duraine, Lita ; Zuo, Zhongyuan ; Park, Ye Jin ; Li-Kroeger, David ; Bi, Weimin ; Wong, Lee Jun ; Rosenfeld, Jill ; Gleeson, Joseph ; Faqeih, Eissa ; Alkuraya, Fowzan S. ; Wierenga, Klaas J. ; Chen, Jiani ; Afenjar, Alexandra ; Nava, Caroline ; Doummar, Diane ; Keren, Boris ; Juusola, Jane ; Grompe, Markus ; Bellen, Hugo J. ; Campeau, Philippe M. / Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. In: American Journal of Human Genetics. 2019 ; Vol. 105, No. 6. pp. 1237-1253.
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T1 - Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

AU - Wang, Julia

AU - Rousseau, Justine

AU - Kim, Emily

AU - Ehresmann, Sophie

AU - Cheng, Yi Ting

AU - Duraine, Lita

AU - Zuo, Zhongyuan

AU - Park, Ye Jin

AU - Li-Kroeger, David

AU - Bi, Weimin

AU - Wong, Lee Jun

AU - Rosenfeld, Jill

AU - Gleeson, Joseph

AU - Faqeih, Eissa

AU - Alkuraya, Fowzan S.

AU - Wierenga, Klaas J.

AU - Chen, Jiani

AU - Afenjar, Alexandra

AU - Nava, Caroline

AU - Doummar, Diane

AU - Keren, Boris

AU - Juusola, Jane

AU - Grompe, Markus

AU - Bellen, Hugo J.

AU - Campeau, Philippe M.

PY - 2019/12/5

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N2 - 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.

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