Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

• DOI: 10.1038/362059a0
• Publication Date: 2003-08-12T00:21:22Z
• Authors: Daniel R. Rosen; Teepu Siddique; David Patterson; Denise A. Figlewicz; Peter Sapp; Afif Hentati; Deirdre Donaldson; Jun Goto; Jeremiah P. O'Regan; Han-Xiang Deng; Zohra Rahmani; Aldis Krizus; Diane McKenna-Yasek; Annarueber Cayabyab; Sandra M. Gaston; Ralph Berger; Rudolph E. Tanzi; John J. Halperin; Brian Herzfeldt; Raymond Van den B...; Wu-Yen Hung; Thomas Bird; Gang Deng; Donald W. Mulder; Celestine Smyth; Nigel G. Laing; Edwin Soriano; Margaret A. Peric...; Jonathan Haines; Guy A. Rouleau; James S. Gusella; H. Robert Horvitz; Robert H. Brown
• Keywords: 0303 health sciences; Polymorphism, Genetic; Base Sequence; Sequence Homology, Amino Acid; Genome, Human; Superoxide Dismutase; Amyotrophic Lateral Sclerosis; Molecular Sequence Data; DNA; Exons; Polymerase Chain Reaction; 3. Good health; Isoenzymes; 03 medical and health sciences; Oligodeoxyribonucleotides; Mutation; Animals; Humans; Nucleic Acid Conformation; Amino Acid Sequence; Lod Score; Codon; Repetitive Sequences, Nucleic Acid

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.