ECEL1 – Distal Arthrogryposis Type 5D

Distal arthrogryposis type 5D (DA5D) is a rare autosomal recessive limb contracture syndrome characterized by congenital distal joint contractures, camptodactyly, neck pterygia, ptosis, microretrognathia, scoliosis, and other dysmorphic features. The causative gene, ECEL1, encodes a membrane-bound metalloprotease essential for motor nerve terminal arborization and neuromuscular junction formation during prenatal development.

Genetic studies have identified biallelic ECEL1 variants in multiple unrelated probands with DA5D. A novel homozygous splice-site mutation c.1184+1G>T was reported in an Emirati child presenting with camptodactyly and neck pterygium ([PMID:28114145]). A familial case from Pakistan harbored a homozygous missense variant c.158C>A (p.Pro53Gln) in ECEL1 in a child with knee extension contractures, clubfoot, ptosis, and scoliosis ([PMID:31555621]). Additional compound heterozygous and homozygous LoF and missense variants have been described across diverse populations, including Sardinian founder c.1507-9G>A ([PMID:33672664]) and an Indian cohort carrying c.1184G>A (p.Arg395Gln) in nine affected individuals ([PMID:38568023]).

The variant spectrum in ECEL1 includes: splice-site (e.g., c.1184+1G>T), missense (e.g., c.158C>A (p.Pro53Gln)), nonsense (e.g., c.69C>A (p.Cys23Ter)), and frameshift mutations. Founder alleles have been observed in isolated populations, and recurrent missense mutations expand the allelic heterogeneity. Carrier frequencies remain extremely low in population databases.

Functional knock-in mouse models carrying pathogenic ECEL1 missense mutations (Cys760Arg and Gly607Ser) recapitulate human DA5D phenotypes, demonstrating defective motor axon arborization, abducens nerve guidance defects, and differential effects on ECEL1/DINE mRNA and protein localization in motor neurons ([PMID:29132416]). These data support a loss-of-function mechanism leading to impaired neuromuscular junction formation.

No conflicting or refuting evidence has been reported; all studies consistently associate ECEL1 biallelic mutations with DA5D. Experimental and genetic data are concordant across independent reports and model organisms.

Collectively, the genetic and functional evidence supports a definitive association between ECEL1 and autosomal recessive DA5D. Molecular confirmation of ECEL1 pathogenic variants enables accurate genetic counselling, prenatal diagnosis, and targeted follow-up for affected families.

Key Take-home: ECEL1 biallelic loss-of-function and missense variants cause autosomal recessive distal arthrogryposis type 5D, with consistent clinical features and supportive functional data, informing diagnostic and counseling strategies.

References

• Medical Principles and Practice • 2017 • A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child. PMID:28114145
• Frontiers in Pediatrics • 2019 • Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D). PMID:31555621
• International Journal of Molecular Sciences • 2021 • A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D. PMID:33672664
• American Journal of Medical Genetics Part A • 2024 • ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant. PMID:38568023
• Acta Neuropathologica Communications • 2017 • Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders. PMID:29132416

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