title: Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.
abstract: 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.
authors.affiliation: Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Sant Antoni Ma. Claret 167, 08025 Barcelona, Spain. lalias@santpau.cat
authors.forename: Laura
authors.initials: L
authors.lastname: Alías
authors.forename: Sara
authors.initials: S
authors.lastname: Bernal
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: María Jesus
authors.initials: MJ
authors.lastname: Barceló
authors.forename: Eva
authors.initials: E
authors.lastname: Also
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martínez-Hernández
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rodríguez-Alvarez
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Martín
authors.forename: Elena
authors.initials: E
authors.lastname: Aller
authors.forename: Elena
authors.initials: E
authors.lastname: Grau
authors.forename: Ana
authors.initials: A
authors.lastname: Peciña
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.forename: Enrique
authors.initials: E
authors.lastname: Galán
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Rosa
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Burriel
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: José M
authors.initials: JM
authors.lastname: Millán
authors.forename: Concepción
authors.initials: C
authors.lastname: Hernández-Chico
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Tizzano
mesh_terms: 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*
chemical_list: C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein