Identification of candidate genes in patients with amyotrophic lateral sclerosis by breakpoint characterisation

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons in the brain and spinal cord. Familial forms of ALS (FALS) account for 5–10% of all ALS patients and to date two disease genes, SOD1 and ALS2, have been identified.

Genetic causes of the sporadic forms of ALS (SALS) are still unknown.

We have investigated five patients with SALS carrying balanced chromosomal rearrangements (t(4;19) (q22;p13.1), t(4;20) (p15.3;q11.2), t(18;21) (q23;q22.1), inv(12) (p11q13), inv(X) (p11.2q21.3)) in order to identify SALS underlying genetic factors.

By fluorescence in situ hybridization, we have narrowed all breakpoints to intervals of 100 kb or less. In three patients the breakpoint regions harbour interesting candidate genes that may have an impact on the etiology of SALS.

In the case of the inversion 12, multiple candidate genes have been found, including ITGA7, which encodes the integrin alpha chain 7, GCN5L1 encoding the general control of amino-acid synthesis 5-like 1, and the uncharacterized ARG99 gene. In the translocation t(18;21), the chromosome 21 breakpoint interval of 70 kb contains the GRIK1 gene, a glutamte receptor subunit whereas molecular analysis for 18q23 did not provide an indication for a disrupted gene. In the translocation t(4;19) fine-mapping of the breakpoints by Southern hybridization showed that on each site an as yet uncharacterised transcript may be affected by the rearrangement. Further characterization of these transcripts and mutation analysis in identified candidate genes will soon shed more light on their relevance in SALS.