Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.
Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II-III) predominated in males (p<0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1-SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T>G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN-SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein.
Alías
Laura
L
Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Sant Antoni Ma. Claret 167, 08025 Barcelona, Spain. lalias@santpau.cat
Bernal
Sara
S
Fuentes-Prior
Pablo
P
Barceló
María Jesus
MJ
Also
Eva
E
Martínez-Hernández
Rebeca
R
Rodríguez-Alvarez
Francisco J
FJ
Martín
Yolanda
Y
Aller
Elena
E
Grau
Elena
E
Peciña
Ana
A
Antiñolo
Guillermo
G
Galán
Enrique
E
Rosa
Alberto L
AL
Fernández-Burriel
Miguel
M
Borrego
Salud
S
Millán
José M
JM
Hernández-Chico
Concepción
C
Baiget
Montserrat
M
Tizzano
Eduardo F
EF
D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D013030:Spain; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein