Mutations in ECEL1 cause distal arthrogryposis type 5D

Abstract

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.

Figure 1

Pedigree and Clinical Features of Family A Pedigree showing the relationships and affected status of family A. Typical features of the face include unilateral ptosis, a round-shaped face, a small jaw, a bulbous upturned nose, and arched eyebrows. Camptodactyly and severely adducted thumbs are also present. Case identifiers A:V-1 (images A and D), A:IV-6 (images B and E [left]), and A:IV-5 (images C and E [right]) correspond to those in Table 1, where a detailed description of each individual is provided. The proband is indicated with an arrow. Asterisks indicate individuals in whom whole-genome sequencing (WGS) was performed. Red dots indicate individuals from whom genotype data were included in analysis of linkage under a recessive model. Open red squares indicate individuals who were included in the recessive model and from whom genotype data were unavailable. Blue dots indicate individuals from whom genotype data were included in analysis of linkage under a dominant model. Open blue squares indicate individuals who were included in the dominant model and from whom genotype data were unavailable. Larger and more detailed images are presented in Figures S1 and S4.

Figure 2

Genomic Structure and Allelic Spectrum of ECEL1 Mutations that Cause DA5D ECEL1 is composed of 18 exons that encode UTRs (orange) and protein-coding-sequence domains (blue), including cytoplasmic (red), transmembrane (orange), and extracellular (gold) domains and the activation site (black). Arrows indicate the locations of nine different mutations found in five families affected by DA5D. The † symbol indicates mutations that were confirmed to be inherited from the parents.