title: Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.
abstract: Mutations in NIPA1 cause hereditary spastic paraplegia type 6 (SPG6 HSP). Sequencing of the whole gene has revealed alterations of either of two nucleotides in eight of nine SPG6 HSP families reported to date. By analysing CpG methylation, we provide a mechanistic explanation for a mutational hotspot to underlie frequent alteration of one of these nucleotides. We also developed PCR RFLP assays to detect recurrent NIPA1 changes and screened 101 independent HSP patients, including 45 index patients of autosomal dominant HSP families. Our negative finding in this cohort for which several other causes of HSP had been excluded suggests NIPA1 alterations at mutational hotspots to be less frequent than previously thought. Nevertheless, the assays introduced represent a valid pre-screen easily implementable in the molecular diagnosis of HSP.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum, 07747 Jena, Germany. christian.beetz@med.uni-jena.de
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Stephan
authors.initials: S
authors.lastname: Klebe
authors.forename: Sven
authors.initials: S
authors.lastname: Klimpe
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacour
authors.forename: Susanne
authors.initials: S
authors.lastname: Otto
authors.forename: Anne-Dorte
authors.initials: AD
authors.lastname: Sperfeld
authors.forename: Bart
authors.initials: B
authors.lastname: van de Warrenburg
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Thomas
authors.initials: T
authors.lastname: Deufel
mesh_terms: D015331:Cohort Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C478824:NIPA1 protein, human