Research press release


Nature Medicine

Genetics: Causative gene for early-onset ALS identified



C Bönnemannたちは、7つの家系に属する重度の早期発症型ALS患者9人のゲノム塩基配列を解読し、脂質代謝に関わる酵素の構成成分をコードする単一の遺伝子SPTLC1に、まれな一群の変異があることを突き止めた。そして、ALSの原因となるこれらの新しく見つかった変異によって、スフィンゴ脂質の産生が抑制されなくなって、ヒトの運動ニューロン(ALSで特異的に変性するタイプのニューロン)中に蓄積することが、実験により明らかになった。


A specific class of rare mutations in the gene SPTLC1 — which encodes a key metabolic molecule responsible for the production of a class of lipids called sphingolipids — exists in children with severe, early-onset amyotrophic lateral sclerosis (ALS). Clinical findings reported in Nature Medicinereveal both a single genetic cause of early-onset ALS and a novel, metabolism-associated, molecular pathway that may contribute to neurodegeneration in other forms of the disease.

ALS is a progressive neurodegenerative disease that often results in death within 3–5 years of disease onset. Most cases occur sporadically, with important insights into the key drivers of ALS gained from clinical studies linking single-gene mutations directly to the disease.

Carsten Bönnemann and colleagues sequenced the genomes of nine ALS patients from seven families who developed a severe, early-onset form of ALS. The authors identify a rare set of mutations in a single gene — SPTLC1 — that encodes a component of an enzyme involved in lipid metabolism. Experiments revealed that these newly discovered ALS-causing mutations result in unrestrained sphingolipid production and accumulation in human motor neurons — the type of neurons that specifically degenerate in the disease.

This clinical study not only describes a new set of rare, single-gene mutations that underlie an aggressive and early-onset form of ALS, but also suggests that direct metabolic disturbance is a causative factor in disease development.

doi: 10.1038/s41591-021-01346-1


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