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Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships.
Am J Med Genet A. 2019 03; 179(3):373-380.AJ

Abstract

The most frequent cause of isolated complex III deficits is mutations to the nuclear-encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease-causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype-phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under "BCS1L Mitopathies". Patterns in genotype-phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.

Authors+Show Affiliations

Department of Chemistry and Biochemistry, Calvin College, Grand Rapids, Michigan.College of Human Medicine, Michigan State University, Grand Rapids, Michigan.Department of Biology, Calvin College, Grand Rapids, Michigan.Department of Chemistry and Biochemistry, Calvin College, Grand Rapids, Michigan.Spectrum Health Medical Group, Department of Medical Genetics, Grand Rapids, Michigan.

Pub Type(s)

Case Reports
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30582773

Citation

Baker, Rachael A., et al. "Clinical Spectrum of BCS1L Mitopathies and Their Underlying Structural Relationships." American Journal of Medical Genetics. Part A, vol. 179, no. 3, 2019, pp. 373-380.
Baker RA, Priestley JRC, Wilstermann AM, et al. Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. Am J Med Genet A. 2019;179(3):373-380.
Baker, R. A., Priestley, J. R. C., Wilstermann, A. M., Reese, K. J., & Mark, P. R. (2019). Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. American Journal of Medical Genetics. Part A, 179(3), 373-380. https://doi.org/10.1002/ajmg.a.61019
Baker RA, et al. Clinical Spectrum of BCS1L Mitopathies and Their Underlying Structural Relationships. Am J Med Genet A. 2019;179(3):373-380. PubMed PMID: 30582773.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships. AU - Baker,Rachael A, AU - Priestley,Jessica R C, AU - Wilstermann,Amy M, AU - Reese,Kalina J, AU - Mark,Paul R, Y1 - 2018/12/24/ PY - 2018/10/04/received PY - 2018/11/20/revised PY - 2018/11/23/accepted PY - 2018/12/26/pubmed PY - 2020/4/17/medline PY - 2018/12/25/entrez KW - BCS1L KW - complex III deficiency KW - novel mutation KW - structural analysis SP - 373 EP - 380 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 179 IS - 3 N2 - The most frequent cause of isolated complex III deficits is mutations to the nuclear-encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Björnstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease-causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype-phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under "BCS1L Mitopathies". Patterns in genotype-phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L. SN - 1552-4833 UR - https://wwww.unboundmedicine.com/medline/citation/30582773/Clinical_spectrum_of_BCS1L_Mitopathies_and_their_underlying_structural_relationships_ DB - PRIME DP - Unbound Medicine ER -