Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families.
Hereditary spastic paraplegia (HSP) type 15 is an autosomal recessive (AR) form of complicated HSP mainly characterized by slowly progressive spastic paraplegia, mental retardation, intellectual deterioration, maculopathy, distal amyotrophy, and mild cerebellar signs that has been associated with the Kjellin syndrome. The locus for this form of HSP, designated SPG15, was mapped to an interval of 19 cM on chromosome 14q22-q24 in two Irish families. We performed a clinical-genetic study of this form of HSP on 147 individuals (64 of whom were affected) from 20 families with AR-HSP. A genome-wide scan was performed in three large consanguineous families of Arab origin after exclusion of linkage to several known loci for AR-HSP (SPG5, SPG7, SPG21, SPG24, SPG28, and SPG30). The 17 other AR-HSP families were tested for linkage to the SPG15 locus. Only the three large consanguineous families showed evidence of linkage to the SPG15 locus (2.4 > Z (max) > 4.3). Recombinations in these families reduced the candidate region from approximately 16 to approximately 5 Mbases. Among the approximately 50 genes assigned to this locus, two were good candidates by their functions (GPHN and SLC8A3), but their coding exons and untranslated regions (UTRs) were excluded by direct sequencing. Patients had spastic paraplegia associated with cognitive impairment, mild cerebellar signs, and axonal neuropathy, as well as a thin corpus callosum in one family. The ages at onset ranged from 10 to 19 years. Our study highlights the phenotypic heterogeneity of SPG15 in which mental retardation or cognitive deterioration, but not all other signs of Kjellin syndrome, are associated with HSP and significantly reduces the SPG15 locus.
INSERM, U679, Groupe Hospitalier Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France.
Nizar
N
Elleuch
Naima
N
Bouslam
Sylvain
S
Hanein
Alexander
A
Lossos
Abdelmadjid
A
Hamri
Stephan
S
Klebe
Vardiella
V
Meiner
Nezha
N
Birouk
Israela
I
Lerer
Djamel
D
Grid
Delphine
D
Bacq
Meriem
M
Tazir
Diana
D
Zelenika
Zohar
Z
Argov
Alexandra
A
Durr
Mohamed
M
Yahyaoui
Ali
A
Benomar
Alexis
A
Brice
Giovanni
G
Stevanin
D000293:Adolescent; D000328:Adult; D018912:Arabs / Q000235:genetics; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D003241:Consanguinity; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000523:psychology; D013577:Syndrome