Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.
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.
Beetz
Christian
C
Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum, 07747 Jena, Germany. christian.beetz@med.uni-jena.de
Schüle
Rebecca
R
Klebe
Stephan
S
Klimpe
Sven
S
Klopstock
Thomas
T
Lacour
Arnaud
A
Otto
Susanne
S
Sperfeld
Anne-Dorte
AD
van de Warrenburg
Bart
B
Schöls
Ludger
L
Deufel
Thomas
T
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*
D008565:Membrane Proteins; C478824:NIPA1 protein, human