Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene

• Published in: Human genetics Vol. 125; no. 1; pp. 29 - 39
• Main Authors: Alías, Laura, Bernal, Sara, Fuentes-Prior, Pablo, Barceló, María Jesus, Also, Eva, Martínez-Hernández, Rebeca, Rodríguez-Alvarez, Francisco J., Martín, Yolanda, Aller, Elena, Grau, Elena, Peciña, Ana, Antiñolo, Guillermo, Galán, Enrique, Rosa, Alberto L., Fernández-Burriel, Miguel, Borrego, Salud, Millán, José M., Hernández-Chico, Concepción, Baiget, Montserrat, Tizzano, Eduardo F.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-02-2009; Springer; Springer Nature B.V
• Subjects: Analysis; Atrophy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Classical genetics, quantitative genetics, hybrids; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diseases of striated muscles. Neuromuscular diseases; DNA Mutational Analysis; Female; Fundamental and applied biological sciences. Psychology; Gender; Gene Function; Genes; Genetic aspects; Genetic screening; Genetics of eukaryotes. Biological and molecular evolution; Human; Human Genetics; Humans; Male; Medical research; Medical sciences; Medicine, Experimental; Metabolic Diseases; Molecular Medicine; Molecular Sequence Data; Muscular Atrophy, Spinal - genetics; Mutation; Neurology; Original Investigation; Spain; Spinal muscular atrophy; Survival of Motor Neuron 1 Protein - genetics; Europe; Spain; Madrid Spain; Spinal Muscular Atrophy Patient; Survival Motor Neuron; SMN1 Gene; Spinal Muscular Atrophy; Spinal Muscular Atrophy Type; Characterization; Human; Nervous system diseases; Neuromuscular diseases; Gene; Spinal amyotrophy; Central nervous system disease; Genetics; Degenerative disease; Identification; Mutation; Spinal cord disease
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-008-0598-1

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.