A novel locus for autosomal dominant uncomplicated hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

• Published in: Human genetics Vol. 122; no. 3-4; pp. 261 - 273
• Main Authors: HANEIN, Sylvain, DÜRR, Alexandra, BRICE, Alexis, STEVANIN, Giovanni, RIBAI, Pascale, FORLANI, Sylvie, LEUTENEGGER, Anne-Louise, NELSON, Isabelle, BABRON, Marie-Claude, ELLEUCH, Nizar, DEPIENNE, Christel, CHARON, Céline
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.11.2007; Berlin Springer Nature B.V; New York, NY
• Subjects: Adolescent; Adult; Age of Onset; Aged; Biological and medical sciences; Child; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 10 - genetics; Chromosomes, Human, Pair 8 - genetics; Classical genetics, quantitative genetics, hybrids; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Fundamental and applied biological sciences. Psychology; Genes; Genes, Dominant; Genetic Markers; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Human; Humans; Kinesin - genetics; Lod Score; Male; Medical sciences; Methods, theories and miscellaneous; Microsatellite Repeats; Middle Aged; Mutation; Nerve Tissue Proteins - genetics; Neuregulin-1; Neurology; Paralysis; Patients; Pedigree; Spastic Paraplegia, Hereditary - genetics; Spasticity; France; Paris France; Genetic mapping; Hereditary spastic paraplegia; Nervous system diseases; Central nervous system disease; Genetics; Degenerative disease; Autosome; Locus; Spinal cord disease; Genetic disease; Cerebral disorder
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-007-0396-1

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.