title: Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia.
abstract: Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder selectively affecting axons of spinal cord motoneurons. Classical mutations in the most frequent HSP gene SPAST (spastin protein) act through haploinsufficiency by abolishing the activity of a C-terminal ATPase domain or by interfering with expression from the affected allele. N-terminal missense variants have been suggested to represent rare polymorphisms, to cause unusually mild phenotypes, and to aggravate the effect of a classical mutation. We confirm these associations for p.S44L but do not detect two other variants (p.E43Q; p.P45Q) in HSP patients and controls. We show that neither of several disease mechanisms associated with classical SPAST mutations applies to the N-terminal variants. Instead, all three alterations enhance the stability of one of two alternative spastin isoforms. Their phenotypic effect may thus not be mediated by haploinsufficiency but by increasing isoform competition for interacting proteins, substrates or oligomerization partners.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schickel
authors.forename: T
authors.initials: T
authors.lastname: Pamminger
authors.forename: A
authors.initials: A
authors.lastname: Ehrsam
authors.forename: S
authors.initials: S
authors.lastname: Münch
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Klopstock
authors.forename: G
authors.initials: G
authors.lastname: Kurlemann
authors.forename: P
authors.initials: P
authors.lastname: Hemmerich
authors.forename: W
authors.initials: W
authors.lastname: Dubiel
authors.forename: T
authors.initials: T
authors.lastname: Deufel
authors.forename: C
authors.initials: C
authors.lastname: Beetz
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D000074181:Spastin
chemical_list: D020033:Protein Isoforms; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human