Expanding the phenotypic spectrum of <i>ECEL1</i>‐related congenital contracture syndromes

Shaaban, Sherin; Düzcan, Füsun; Yıldırım, Cem; Chan, Wai‐Man; Andrews, Caroline; Akarsu, Nurten; Engle, Elizabeth C.

doi:10.1111/cge.12224

Cited by 26 publications

(37 citation statements)

References 31 publications

(55 reference statements)

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“…Previous clinical studies have reported that mutations of human homologue ECEL1 are responsible for DA, and DA patients usually display multiple contractures, especially in the upper limbs (i.e., hand, wrist, and elbow contractures) and lower limbs (i.e., foot, ankle, knee, and hip joint contractures) [9,19,27,28]. Although the pathogenesis of the disease remains poorly understood, our systematic Fig.…”

Section: Discussionmentioning

confidence: 79%

“…The ECEL1 mutation is observed in type DA5, which is largely characterized by ocular phenotypes (ptosis, ophthalmoplegia, and/or strabismus), in addition to the limb contracture phenotypes common to other DA types. In terms of these ocular phenotypes, two reports have suggested that ECEL1 mutation also leads to congenital cranial dysinnervation disorders (CCDD), which are the result of developmental errors in cranial musculature innervation [16,27]. Because DINE is expressed in all cranial and spinal motoneurons from early embryonic stages in rodents [20], cranial motor innervations could also be affected by a deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past 2 years, a number of single nucleotide changes in the human homologue ECEL1 locus have been identified as causal mutations of DA [3,9,19,23,27,28]. They include some nonsense mutations, which lead to loss of full-length protein, as well as some missense mutations with only one amino acid exchange.…”

Section: Generation Of Dine Knock-in Mice With a Pathogenic Da Mutatimentioning

confidence: 99%

“…muscles could be the major pathogenesis of DA [10,29,30]. More recently, several independent groups reported that endothelin-converting enzyme-like 1 (ECEL1), a membrane-bound metalloprotease, is the responsible gene for type 5 DA (DA5) (MIM 108145) [3,9,19,23,27,28]. In the case of ECEL1, DA shows autosomal recessive inheritance, and patients commonly display limb contracture, as well as severe skeletal muscle atrophy in their limb [9].…”

Section: Introductionmentioning

confidence: 99%

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ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

et al. 2016

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The membrane-bound metalloprotease endothelin-converting enzyme-like 1 (ECEL1) has been newly identified as a causal gene of a specific type of distal arthrogryposis (DA). In contrast to most causal genes of DA, ECEL1 is predominantly expressed in neuronal cells, suggesting a unique neurogenic pathogenesis in a subset of DA patients with ECEL1 mutation. The present study analyzed developmental motor innervation and neuromuscular junction formation in limbs of the rodent homologue damage-induced neuronal endopeptidase (DINE)-deficient mouse. Whole-mount immunostaining was performed in DINE-deficient limbs expressing motoneuron-specific GFP to visualize motor innervation throughout the limb. Although DINE-deficient motor nerves displayed normal trajectory patterns from the spinal cord to skeletal muscles, they indicated impaired axonal arborization in skeletal muscles in the forelimbs and hindlimbs. Systematic examination of motor innervation in over 10 different hindlimb muscles provided evidence that DINE gene disruption leads to insufficient arborization of motor nerves after arriving at the skeletal muscle. Interestingly, the axonal arborization defect in foot muscles appeared more severe than in other hindlimb muscles, which was partially consistent with the proximal-distal phenotypic discordance observed in DA patients. Additionally, the number of innervated neuromuscular junction was significantly reduced in the severely affected DINE-deficient muscle. Furthermore, we generated a DINE knock-in (KI) mouse model with a pathogenic mutation, which was recently identified in DA patients. Axonal arborization defects were clearly detected in motor nerves of the DINE KI limb, which was identical to the DINE-deficient limb. Given that the encoded sequences, as well as ECEL1 and DINE expression profiles, are highly conserved between mouse and human, abnormal arborization of motor axons and subsequent failure of NMJ formation could be a primary cause of DA with ECEL1 mutation.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Generation Of Dine Knock-in Mice With a Pathogenic Da Mutatimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

et al. 2016

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“…The latter findings were corroborated by both Human Splicing Finder and CADD, which yielded a PHRED scaled score of 24.8. Numerous mutations in the ECEL1 gene have been reported recently, and, with the spectrum of clinical features of the associated condition, DA5D is becoming more established with each one [6][7][8] . Many of the characteristic features of DA5D are present in this reported case.…”

Section: Discussionmentioning

confidence: 99%

A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child

Hamzeh

Nair²,

Mohamed³

et al. 2017

Med Princ Pract

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Objective: The aim of this work was to report a case of an Emirati child who presented with developmental delay and multiple congenital abnormalities that are consistent with distal arthrogryposis type 5D. Clinical Presentation and Intervention: The clinical presentation comprised contractures of the shoulders, elbows, and knees in addition to camptodactyly and neck pterygium. The facial dysmorphic features noted include ptosis and microretrognathia. Importantly, left orchidopexy was also observed and corrected surgically. Whole exome sequencing revealed that the patient is homozygous for the novel c.1184+1G>T variant in endothelin-converting enzyme-like 1 (ECEL1). Conclusion: This is a case of a novel homozygous splice site mutation in the ECEL1 gene in a child with a phenotype consistent with distal arthrogryposis type 5D. The child was born to consanguineous Emirati parents heterozygous for the novel ECEL1 mutation.

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Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1

Barnett

Todd

Ong

et al. 2014

American J of Med Genetics Pt A

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Expanding the phenotypic spectrum of ECEL1‐related congenital contracture syndromes

Cited by 26 publications

References 31 publications

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child

Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1

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