title: A novel locus for autosomal dominant "uncomplicated" hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3.
abstract: Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous. Both "uncomplicated" and "complicated" forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Hitherto, ten autosomal dominant "uncomplicated" HSP (ADHSP) loci have been mapped. Here, we report linkage of ADHSP with markers of the 8p21.1-q13.3 chromosomal region in a large French family, including 29 examined at-risk individuals. The age at onset varied from 8 to 60 years with a mean of 31.6 +/- 16.4 years. Multipoint and two-point LOD-score calculations as well as haplotype reconstruction in this region gave support to the location of this novel ADHSP locus (SPG37) in a 43.5 cM genetic interval flanked by loci D8S1839 and D8S1795. The region was shared by all definitely (n = 13), probably (n = 3) and possibly (n = 2) affected patients with a maximum LOD score of 4.20 at the D8S601 locus. Two candidate genes, encoding the kinesin family member 13B and neuregulin 1 (isoforms SMDF and GFF2), were screened for mutations, but no disease-causing alterations were identified. Interestingly, another region, on chromosome 10q22.3-23.31, was found to segregate in all affected patients (but not in probably or possibly affected subjects) and in a high proportion of healthy at risk individuals, suggesting that this locus might act as a modifier of the phenotype.
authors.affiliation: INSERM, Unit 679, 47 Bd de l'Hôpital, 75013 Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Pascale
authors.initials: P
authors.lastname: Ribai
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Leutenegger
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nelson
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Babron
authors.forename: Nizar
authors.initials: N
authors.lastname: Elleuch
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Céline
authors.initials: C
authors.lastname: Charon
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020890:Neuregulin-1; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C513406:KIF13B protein, human; D016547:Kinesins