High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.
BACKGROUND
Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4.


OBJECTIVE
To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP.


METHODS
We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings.


RESULTS
Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations.


CONCLUSIONS
Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.
Beetz
C
C
Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, D-07740 Jena, Germany.
Nygren
A O H
AO
Schickel
J
J
Auer-Grumbach
M
M
Bürk
K
K
Heide
G
G
Kassubek
J
J
Klimpe
S
S
Klopstock
T
T
Kreuz
F
F
Otto
S
S
Schüle
R
R
Schöls
L
L
Sperfeld
A-D
AD
Witte
O W
OW
Deufel
T
T
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics*; D006238:Haploidy; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human