title: SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations.
abstract: Hereditary spastic paraplegias (HSPs) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, mutations in fatty acid 2-hydroxylase gene (FA2H) have been identified responsible for HSPs type 35 (SPG35). This study aims to define the contribution of FA2H to Chinese autosomal recessive HSP (AR-HSP) patients and provide insights into the enzymatic functions of the novel mutations. Direct sequencing of FA2H was conducted in 31 AR-HSP families and 55 sporadic cases without SPG11, SPG15, SPG5 and SPG7 gene mutations. Enzymatic activity of the mutated proteins was further examined. Three novel mutations were found in two Chinese families, including two compound heterozygous mutations (c.388C>T/p.L130F and c.506+6C>G) and one homozygous mutation (c.230T>G/p.L77R). The c.506+6C>G splice-site mutation led to the deletion of exon 3. Measurement of enzymatic functions revealed a significant reduction in the enzymatic activity of FA2H associated with p.L130F and p.L77R. Overall, our data widens the spectrum of the mutations on FA2H, and functional analyses indicate that these mutations severely impair the enzymatic activity of FA2H. Furthermore, frequency analysis shows that SPG35 is the second most common subtype of AR-HSP in China.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: X
authors.initials: X
authors.lastname: Liao
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: Z
authors.initials: Z
authors.lastname: Zhan
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
authors.forename: K
authors.initials: K
authors.lastname: Xia
authors.forename: B
authors.initials: B
authors.lastname: Tang
authors.forename: L
authors.initials: L
authors.lastname: Shen
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D002681:China; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000145:classification / Q000201:enzymology* / Q000473:pathology*
chemical_list: D022821:RNA Splice Sites; D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase
keywords: FA2H; SPG35; fatty acid hydroxylase-associated neurodegeneration (FAHN); hereditary spastic paraplegia