GLE1 and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons, leading to muscle weakness and respiratory failure. GLE1 encodes a conserved mRNA export factor localized at the nuclear pore complex, essential for nucleocytoplasmic shuttling of mRNA. Although homozygous GLE1 mutations cause lethal congenital contracture syndromes, emerging evidence implicates heterozygous GLE1 variants in adult-onset ALS.

Initial screening of 250 Han Chinese ALS patients found no nonsynonymous GLE1 coding variants, indicating rarity in this population (PMID:29398120). A larger cohort study of 173 familial and 760 sporadic ALS cases identified three heterozygous deleterious GLE1 variants—one splice-site (c.1965-2A>C), one nonsense, and one missense mutation—among 933 patients (PMID:25343993). More recently, sequencing of 628 Chinese ALS patients and 522 controls uncovered seven rare GLE1 coding variants, including a novel nonsense allele; loss-of-function variants occurred at a frequency of 0.16% in sporadic cases (PMID:34025336).

All ALS-associated GLE1 mutants tested failed to rescue motor neuron defects in zebrafish morphants lacking endogenous gle1, and in HeLa cells these variants caused depletion of hGle1 at the nuclear pore, impairing mRNA export. These assays demonstrate a haploinsufficiency mechanism aligning with the loss-of-function nature of the identified alleles (PMID:25343993). No segregation data are available for these variants, precluding assessment of familial penetrance.

Integration of genetic and experimental findings supports a Moderate clinical validity classification for the GLE1–ALS association. Although GLE1 variants are infrequent, the identification of deleterious alleles in multiple unrelated ALS patients accompanied by concordant functional impairment underscores a contributory role. Expanded GLE1 sequencing in ALS cohorts and detailed segregation analyses will refine penetrance estimates and inform patient management.

Key take-home: Rare heterozygous GLE1 loss-of-function variants contribute to ALS via haploinsufficiency, supporting inclusion of GLE1 in diagnostic gene panels for motor neuron disease.

References

• Human molecular genetics • 2015 • Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. PMID:25343993
• Neurobiology of aging • 2018 • Screening of GLE1 mutations in Chinese amyotrophic lateral sclerosis patients. PMID:29398120
• Frontiers in neuroscience • 2021 • Mutation Screening of the GLE1 Gene in a Large Chinese Cohort of Amyotrophic Lateral Sclerosis Patients. PMID:34025336

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