GLE1 – Lethal congenital contracture syndrome 1

GLE1 encodes an mRNA export mediator essential for nucleocytoplasmic transport. Biallelic loss‐of‐function and splice‐site variants in GLE1 cause lethal congenital contracture syndrome 1 (LCCS1; MONDO:0009670), a severe autosomal recessive motor neuron disease characterized by fetal akinesia, joint contractures, and perinatal lethality.

Clinically, GLE1‐related LCCS1 presents with arthrogryposis multiplex congenita (HP:0002804), respiratory failure (HP:0002878), and often seizures (HP:0001250). The FinMajor splice founder variant (c.432‐10A>G) is highly prevalent in Finland, and novel compound heterozygous splice mutations have been reported in non-Finnish families. Three unrelated families (six probands) with biallelic GLE1 variants have been described, all with consistent autosomal recessive segregation and early lethality ([PMID:27684565]; [PMID:28657126]; [PMID:32537934]).

Inheritance is autosomal recessive. To date, six probands from three families harbor combinations of splice‐site mutations (e.g., c.1243-2A>G), frameshifts, and nonsense variants. The variant spectrum is dominated by premature termination codons and essential splice defects. A recurrent missense allele, c.2051T>C (p.Ile684Thr), demonstrated pathogenicity in a homozygous state in two siblings who survived to 6 months ([PMID:28657126]).

Functional studies support a loss-of-function mechanism. In patient fibroblasts, residual wild-type transcript correlates with extended survival ([PMID:27684565]). In zebrafish, gle1 deficiency recapitulates motor neuron loss, apoptosis of neural precursors, and motor axon arborization defects, all rescued by wild-type human GLE1 but not by the FinMajor mutant ([PMID:22357925]). Structural analyses show that disease alleles disrupt Gle1 oligomerization and mRNA export activity ([PMID:24243016]).

No conflicting reports have emerged to dispute the GLE1–LCCS1 association. Together, genetic segregation across multiple families, a clear recessive inheritance pattern, and convergent functional data establish a "Moderate" clinical validity based on ClinGen criteria.

Key Take-home: Biallelic GLE1 truncating and splice mutations cause autosomal recessive LCCS1 with a predictable neuromuscular phenotype, informing molecular diagnosis and genetic counseling.

References

• Clinical Genetics • 2017 • Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum. PMID:27684565
• Clinical Genetics • 2018 • A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss. PMID:28657126
• Molecular Genetics & Genomic Medicine • 2020 • Extension of the phenotypic spectrum of GLE1-related disorders to a mild congenital form resembling congenital myopathy. PMID:32537934
• Development (Cambridge, England) • 2012 • A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in spinal neural precursor survival and motor axon arborization. PMID:22357925
• Cell • 2013 • Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. PMID:24243016

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