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ECEL1
endothelin converting enzyme like 1
ECEL1 is located on the long (q) arm of chromosome 2, at band 2q37.1. Arm ratio per GRCh38 - banding schematic.
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Overview
ECEL1 is located on chromosome 2 and encodes endothelin converting enzyme-like 1, a member of the neprilysin family of zinc-dependent metalloproteases. The protein functions primarily during foetal development, where it is thought to process bioactive peptides that regulate muscle differentiation and neuromuscular junction formation. Pathogenic variants in ECEL1 follow an autosomal recessive inheritance pattern, meaning that affected individuals typically inherit altered copies from both parents. The gene is recognised on several NHS Genomic Medicine Service panels for conditions affecting muscle development and joint mobility from birth.
What the gene does
The ECEL1 protein acts as a metalloprotease enzyme, catalysing the cleavage of peptide bonds in specific signalling molecules. This enzymatic activity requires zinc ions coordinated within the active site, typical of the M13 peptidase family. During embryonic and foetal development, ECEL1 is expressed in skeletal muscle and nervous tissue, where it is believed to process endothelin-related peptides and potentially other substrates involved in cellular signalling pathways. The protein's catalytic function appears particularly important for establishing proper neuromuscular connectivity and coordinating muscle fibre maturation. Loss of ECEL1 activity disrupts these developmental processes, affecting the structural organisation of muscles and the formation of functional joints. The precise substrate repertoire of ECEL1 remains an active area of research, but evidence suggests its proteolytic activity is essential for normal limb patterning and muscle contractile apparatus assembly.
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Chromosome location
ECEL1 is positioned at chromosome band 2q37.1, near the telomeric end of the long arm of chromosome 2. This chromosomal region contains several other genes involved in developmental processes. The gene spans multiple exons that are transcribed and spliced to produce the mature messenger RNA template for protein synthesis.
Protein structure
The ECEL1 protein comprises 775 amino acids and contains a Peptidase M13 domain spanning amino acids 98 to 775. This domain encompasses the catalytic core responsible for the protein's metalloprotease activity, including conserved motifs that coordinate the essential zinc ion cofactor. The N-terminal region preceding the peptidase domain may contribute to protein localisation or regulatory interactions, though detailed structural characterisation of this segment remains limited. The extended Peptidase M13 domain occupies the majority of the protein length, reflecting ECEL1's primary role as a catalytic enzyme rather than a scaffold or regulatory protein.
Key variants
Pathogenic variants in ECEL1 typically result in loss of enzymatic function through mechanisms such as premature termination, frameshift mutations, or missense changes affecting the catalytic domain. Because ECEL1-related conditions follow autosomal recessive inheritance, affected individuals carry variants on both gene copies. The variant spectrum includes nonsense mutations, splice-site alterations, and deletions that disrupt normal protein production or stability. Founder effects have been observed in certain populations, where specific pathogenic variants occur at higher frequencies.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.110_155del | p.Phe37fs | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.1184G>A | p.Arg395Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.1303C>T | p.Gln435Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.1470G>A | p.Trp490Ter | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.1685+1G>A | - | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.2023G>A | p.Ala675Thr | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.509del | p.Gly170fs | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.80del | p.Gly27fs | Pathogenic/Likely pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.966+1G>A | - | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
c.997C>T | p.Arg333Ter | Pathogenic | ★★☆☆ | Distal arthrogryposis type 5D |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in ECEL1 are associated with distal arthrogryposis, a group of conditions characterised by congenital joint contractures predominantly affecting the hands and feet. Affected individuals may present with clenched fists, overlapping fingers, and positional foot deformities evident at birth. Some cases also feature features of congenital myopathy, with muscle weakness and hypotonia contributing to the clinical presentation. The severity and specific manifestations can vary among affected individuals, though the core features of joint contractures and reduced foetal movement are typically present. Early diagnosis through genetic testing can inform clinical management and family planning discussions.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ECEL1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
ECEL1 is included on multiple NHS Genomic Medicine Service panels, reflecting its clinical relevance for diagnosing inherited developmental conditions. The gene holds green (high-evidence) classification on the Arthrogryposis panel (R83), Congenital Myopathy panel (R81), Fetal Anomalies panel (R21), and the Developmental Disorders Genotype-to-Phenotype (DDG2P) database. This green rating indicates strong evidence supporting the gene-disease relationship, meaning that ECEL1 testing is available through NHS genomic testing pathways for individuals presenting with relevant clinical features. Referrals for testing typically occur through clinical genetics services when a patient's presentation aligns with known ECEL1-associated phenotypes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does ECEL1 follow?
ECEL1-related conditions follow autosomal recessive inheritance, meaning an affected individual inherits one pathogenic variant from each parent. Parents who each carry one variant are typically unaffected and have a 25% chance with each pregnancy of having an affected child.
Can ECEL1 variants be detected before birth?
When ECEL1 pathogenic variants are known in a family, prenatal testing and preimplantation genetic testing options may be available. Ultrasound findings such as reduced foetal movement or joint positioning abnormalities may prompt genetic evaluation during pregnancy.
Is ECEL1 testing available on the NHS?
Yes, ECEL1 analysis is available through NHS Genomic Medicine Service testing pathways for individuals meeting clinical criteria for panels including arthrogryposis, congenital myopathy, and foetal anomalies. Referral is typically made through clinical genetics or relevant specialist services.