RT Journal Article
SR Electronic
T1 <em>ACO2</em> homozygous missense mutation associated with complicated hereditary spastic paraplegia
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams &amp; Wilkins
SP e223
DO 10.1212/NXG.0000000000000223
VO 4
IS 2
A1 Christian G. Bouwkamp
A1 Zaid Afawi
A1 Aviva Fattal-Valevski
A1 Inge E. Krabbendam
A1 Stefano Rivetti
A1 Rafik Masalha
A1 Marialuisa Quadri
A1 Guido J. Breedveld
A1 Hanna Mandel
A1 Muhammad Abu Tailakh
A1 H. Berna Beverloo
A1 Giovanni Stevanin
A1 Alexis Brice
A1 Wilfred F.J. van IJcken
A1 Meike W. Vernooij
A1 Amalia M. Dolga
A1 Femke M.S. de Vrij
A1 Vincenzo Bonifati
A1 Steven A. Kushner
YR 2018
UL http://ng.neurology.org/content/4/2/e223.abstract
AB Objective To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).Methods Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.Results A homozygous missense mutation was identified in the ACO2 gene (c.1240T&gt;G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.Conclusions Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.ADP=adenosine diphosphate; ATP=adenosine triphosphate; ExAC=Exome Aggregation Consortium; FCCP=carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HSP=hereditary spastic paraplegia; MAF=minor allele frequency; LCL=lymphoblastoid cell line; LRT=likelihood ratio test; CADD=Combined Annotation Dependent Depletion; RCR=respiratory control ratio; SNP=single nucleotide polymorphism; TCA=tricarboxylic acid cycle