Distal arthrogryposis type 5D with a novel <i>ECEL1</i> gene mutation

Patil, Siddaramappa J.; Kumar, Gaurava; Bhat, Venkatraman; Ramesh, V.; Nagarajaram, Hampapathalu A.; Matalia, Jyoti; Phadke, Shubha R.

doi:10.1002/ajmg.a.36702

Cited by 19 publications

(19 citation statements)

References 14 publications

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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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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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“…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%

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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“…DA5D is clinically characterized by congenital distal joint contractures, knee extension contractures, furrowed tongue, scoliosis, ptosis, and other eye abnormalities (Patil et al, ), but many additional symptoms are reported (McMillin et al, ). To date, there are 39 DA type 5D patients published (Barnett et al, ; Bayram et al, ; Dieterich et al, ; Hamzeh et al, ; McMillin et al, ; Patil et al, ; Shaaban et al, ; Shaheen et al, ), and lately several independent groups have reported endothelin‐converting enzyme‐like 1 ( ECEL1 ), encoding a membrane‐bound metalloprotease, as the responsible gene. Patients with ECEL1 mutations show an autosomal recessive inheritance pattern and commonly display limb contractures, and severe skeletal muscle atrophies (Dieterich et al, ).…”

Section: Introductionmentioning

confidence: 99%

A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases

Stattin

Johansson

Gudmundsson

et al. 2018

American J of Med Genetics Pt A

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Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.

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Distal arthrogryposis type 5D with a novel ECEL1 gene mutation

Cited by 19 publications

References 14 publications

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

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

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

A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases

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