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Novel Pathogenic COX20 Variants Causing Dysarthria, Ataxia, and Sensory Neuropathy Maria G

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Novel Pathogenic COX20 Variants Causing Dysarthria, Ataxia, and Sensory Neuropathy Maria G BRIEF COMMUNICATION Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy Maria G. Otero1,a, Emmanuelle Tiongson2,a, Frank Diaz3, Katrina Haude4, Karin Panzer5, Ashley Collier6, Jaemin Kim1, David Adams7,8, Cynthia J. Tifft7,8, Hong Cui4, Francisca Millian Zamora4, Margaret G. Au9, John M. Graham Jr9, David J. Buckley10, Richard Lewis3, Camilo Toro7,8, Renkui Bai4, Lesley Turner11, Katherine D. Mathews6,12, William Gahl7,8 & Tyler Mark Pierson1,3,9 1Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 2Division of Neurology, Children’s Hospital of Los Angeles, Los Angeles, California 3Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California 4GeneDx, Gaithersburg, Maryland 5Department of Pediatrics, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa 6Provincial Medical Genetics Program, Eastern Health, St. John’s, Newfoundland and Labrador, Canada 7NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland 8Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland 9Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California 10Department of Pediatrics, Janeway Health Centre, St. John’s, Newfoundland and Labrador, Canada 11Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada 12Department of Neurology, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa Correspondence Abstract Tyler M. Pierson, Cedars-Sinai Medical COX20/FAM36A Center, 8700 Beverly Blvd. AHSP 8401, encodes a mitochondrial complex IV assembly factor impor- Los Angeles, CA 90048. Tel: 310-423-4441; tant for COX2 activation. Only one homozygous COX20 missense mutation has Fax: 310-423-1244; been previously described in two separate consanguineous families. We report E-mail: [email protected] four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four Funding Information COX20 During this study D.A., C.J.T. & C.T. were subjects identified the same novel variants. One variant affected the supported by the National Institutes of Health splice donor site of intron-one (c.41A>G), while the other variant Undiagnosed Diseases Network; W.A.G. was (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein supported by the Intramural Research analysis indicated that no full-length cDNA or protein was generated. These Program of the National Human Genome subjects expand the phenotype associated with COX20 deficiency. Research Institute of the National Institutes of Health. TMP was funded by Cedars-Sinai Institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. Received: 26 May 2018; Revised: 4 September 2018; Accepted: 10 September 2018 Annals of Clinical and Translational Neurology 2019; 6(1): 154–160 doi: 10.1002/acn3.661 aContributed equally to this work. 154 ª 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. M. G. Otero et al. COX20 Presenting as Sensory Neuropathy and Ataxia Introduction Materials and Methods COX20 FAM36A (also known as ; MIM#614698) encodes Protocol, patients, and consents a protein with a role in the assembly and stability of mitochondrial complex IV (CIV).1,2 Complex IV is the Protocols were approved through the National Human final component of the respiratory chain and is respon- Genome Research Institute and Cedars-Sinai Medical sible for the reduction of molecular oxygen and oxida- Center (CSMC) institutional review boards (Protocols 76- tion of cytochrome C. Several disorders have been HG-0238 and Pro00037131, respectively) and the families associated with mutations of both nuclear- and mito- gave informed consent. The patients were evaluated at the chondrial-encoded proteins that cause CIV deficiency, University of Iowa Stead Family Children’s Hospital, East- and have presented with encephalopathies, myopathies, ern Health in Newfoundland, Canada, CSMC and at the – and metabolic acidoses.3 7 Previous work indicated that NIH Clinical Center through the NIH Undiagnosed 10,11 COX20 is important for CIV function since COX20-defi- Diseases Program. cient mitochondria accumulated respiratory chain assem- bly intermediates and showed reduced respiratory capacity.2,8 This dysfunction was linked to COX20’s role Exome sequencing in the maturation of the COX2 protein and COX2’s 8 Exome sequencing was performed on family trios as per integration into the CIV holocomplex. previous protocols and the identified genetic variants were Two previous reports identified a rare neurological 2,9 evaluated and classified according to published guidelines disorder associated with COX20 deficiency. Three sub- (GeneDx, Gaithersburg, MD).12,13 jects from two separate consanguineous Turkish families were found to possess the same homozygous COX20 mutation (c.154A>C; p.T52P) and presented with hypo- Cell culture and expression analysis tonia, dystonia, dysarthria, ataxia, and sensory neuropa- 1,9 More detailed information can be found in thy. One family had a child with additional findings Appendix S1. Subject-1’s fibroblasts were grown at 37°C of microcephaly, mildly elevated serum and CSF lactate, 1 under 5% CO2 in Dulbecco’s Modified Eagles Medium and a normal brain MRI. The other family had two (Thermo Fisher Scientific, Waltham, MA) supplemented siblings, a 32-year-old sister and 25-year-old brother, with 10% bovine serum and 1% of penicillin/strepto- with childhood-onset of symptoms along with cerebellar 9 mycin (Thermo Fischer Scientific). RNA was extracted atrophy and sensory neuropathy. Analysis of muscle from cells and reversed transcribed into cDNA. Tran- biopsies from all subjects showed decreased CIV activity. scripts were amplified with primers localizing to exons 1 Protein analysis of fibroblasts revealed an absence of 1,9 or 4, separated on an agarose-gel, and quantified with COX20 protein. Analysis of fibroblast mRNA indicated ImageJ (NIH, Bethesda, MD). Western blots of protein the shared missense variant was also associated with extracts were transferred to a membrane and incubated decreased expression of the full-length mRNA and with primary and secondary antibodies and quantified increased expression of a splice variant that excluded with ImageJ. exon 2 (DEXON2).9 We describe four additional subjects with a COX20- related neurological disorder with features that included Results childhood hypotonia, areflexia, ataxia, dysarthria, dysto- nia, and sensory neuropathy. Exome sequencing identi- Subject-1 COX20 fied the same novel variants in all four subjects, Thirteen-year-old female with infantile hypotonia who + > which included a splice site variant (c.157 3G C) on walked at 14 months and developed progressive ataxia one allele, while the other allele possessed two separate associated with areflexia and dysmetria at 23 months. At > > variants (c.41A G; p.K14R and c.340G A; p.G114S). 5 years, she developed a stuttering dysarthria and episodic mRNA and protein analysis in fibroblasts showed an dystonia. Her gait progressively worsened and she became absence of full-length mRNA and COX20 protein. Fur- nonambulatory at 7 years. She has continued with age- ther analysis revealed this was the result of the appropriate schoolwork. + > c.157 3G C splice donor site variant affecting the splic- Nerve conduction studies at 13 years demonstrated a > ing of exon two and the c.41A G variant affecting the marked sensory neuropathy. The right median sensory splicing of exon one. nerve action potentials (SNAPs) had severely decreased ª 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 155 COX20 Presenting as Sensory Neuropathy and Ataxia M. G. Otero et al. amplitude of 3 lV (normal >20 lV). The right ulnar, During this period, she developed depression, which sural, and radial SNAPs could not be elicited; in contrast, responded to Selective Serotonin Reuptake Inhibitor her motor studies were normal. MRI of the brain at 23 treatment; however, she developed more significant psy- months, 6 years, and 12 years were normal. Spinal MRI chiatric issues that required antipsychotic medication. at 12 years reported that the spinal cord that was “thinner Formal neuropsychological testing at 18 yo showed low- than normal, particularly in the thoracic region” average overall cognitive functioning. She became nonam- (Fig. S1). At 5 years, cerebrospinal fluid analysis showed a bulatory and developed incontinence at 19 years. Cogni- normal basic profile and neurotransmitter metabolites. tive and social skills continued to decline. In her 20s, she Serum evaluation for neuropathy was normal. At 7 years, developed painful muscle spasms that were treated with mitochondrial respiratory chain enzyme analysis of her baclofen. Through her 20s, her condition stabilized with fibroblasts was normal (this is not uncommon with significant disability. mitochondrial fibroblast studies)14,15 (Baylor Genetics,
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