scholarly journals The Novel Compound Heterozygous Mutations of ECEL1 Identified in a Family with Distal Arthrogryposis Type 5D

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Jie-Yuan Jin ◽  
Dan-Yu Liu ◽  
Zi-Jun Jiao ◽  
Yi Dong ◽  
Jie Li ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Clinical Symptoms ◽  
Prenatal Development ◽  
Compound Heterozygous ◽  
Arthrogryposis Multiplex Congenita ◽  
Causative Gene ◽  
Distal Arthrogryposis ◽  
Axonal Arborization ◽  
Motor Nerves ◽  
Compound Heterozygous Mutations

Introduction. Distal arthrogryposis type 5D (DA5D) is an autosomal recessive disease. The clinical symptoms include contractures of the joints of limbs, especially camptodactyly of the hands and/or feet, unilateral ptosis, a round-shaped face, arched eyebrows, and micrognathia, without ophthalmoplegia. ECEL1 is a DA5D causative gene that encodes a membrane-bound metalloprotease. ECEL1 plays important roles in the final axonal arborization of motor nerves in limb skeletal muscles and neuromuscular junction formation during prenatal development. Methods. A DA5D family with webbing of the elbows and fingers was recruited. We performed whole-exome sequencing (WES) and filtered mutations by disease-causing genes of arthrogryposis multiplex congenita (AMC). Mutational analysis and cosegregation confirmation were then performed. Results. We identified novel compound heterozygous mutations of ECEL1 (NM_004826: c.69C>A, p.C23∗ and c.1810G>A, p.G604R) in the proband. Conclusions. We detected causative mutations in a DA5D family, expanding the spectrum of known ECEL1 mutations and contributing to the clinical diagnosis of DA5D.

scholarly journals Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1876
Author(s):  
Julian Theuriet ◽  
Antoine Pegat ◽  
Pascal Leblanc ◽  
Sandra Vukusic ◽  
Cécile Cazeneuve ◽  
...  
Keyword(s):  
Lower Limb ◽  
Clinical Symptoms ◽  
Compound Heterozygous ◽  
Spastic Paraplegia ◽  
The Third ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Compound Heterozygous Mutations ◽  
Biallelic Mutations ◽  
Lateral Sclerosis

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

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

2016 ◽  
Vol 132 (1) ◽  
pp. 111-126 ◽  
Author(s):  
Kenichi Nagata ◽  
Sumiko Kiryu-Seo ◽  
Hiromi Tamada ◽  
Fumi Okuyama-Uchimura ◽  
Hiroshi Kiyama ◽  
...  
Keyword(s):  
Distal Arthrogryposis ◽  
Axonal Arborization ◽  
Motor Nerves

scholarly journals Targeted Double-Stranded cDNA Sequencing-Based Phase Analysis to Identify Compound Heterozygous Mutations and Differential Allelic Expression

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 256
Author(s):  
Hiroki Ura ◽  
Sumihito Togi ◽  
Yo Niida
Keyword(s):  
Phase Analysis ◽  
Genomic Dna ◽  
Allelic Expression ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Cdna Sequencing ◽  
Causative Gene ◽  
Differential Allelic Expression ◽  
In Trans ◽  
Compound Heterozygous Mutations

There are two combinations of heterozygous mutation, i.e., in trans, which carries mutations on different alleles, and in cis, which carries mutations on the same allele. Because only in trans compound heterozygous mutations have been implicated in autosomal recessive diseases, it is important to distinguish them for clinical diagnosis. However, conventional phase analysis is limited because of the large target size of genomic DNA. Here, we performed a genetic analysis on a patient with Wilson disease, and we detected two heterozygous mutations chr13:51958362;G>GG (NM_000053.4:c.2304dup r.2304dup p.Met769HisfsTer26) and chr13:51964900;C>T (NM_000053.4:c.1841G>A r.1841g>a p.Gly614Asp) in the causative gene ATP7B. The distance between the two mutations was 6.5 kb in genomic DNA but 464 bp in mRNA. Targeted double-stranded cDNA sequencing-based phase analysis was performed using direct adapter ligation library preparation and paired-end sequencing, and we elucidated they are in trans compound heterozygous mutations. Trio analysis showed that the mutation (chr13:51964900;C>T) derived from the father and the other mutation from the mother, validating that the mutations are in trans composition. Furthermore, targeted double-stranded cDNA sequencing-based phase analysis detected the differential allelic expression, suggesting that the mutation (chr13:51958362;G>GG) caused downregulation of expression by nonsense-mediated mRNA decay. Our results indicate that targeted double-stranded cDNA sequencing-based phase analysis is useful for determining compound heterozygous mutations and confers information on allelic expression.

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

2014 ◽  
Vol 164 (7) ◽  
pp. 1846-1849 ◽  
Author(s):  
Christopher P. Barnett ◽  
Emily J. Todd ◽  
Royston Ong ◽  
Mark R. Davis ◽  
Vanessa Atkinson ◽  
...  
Keyword(s):  
Clinical Features ◽  
Compound Heterozygous ◽  
Distal Arthrogryposis ◽  
Compound Heterozygous Mutations

Compound-Heterozygous Mutations in the Plasminogen Gene Predispose to the Development of Ligneous Conjunctivitis

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3457-3466 ◽  
Author(s):  
Volker Schuster ◽  
Silvia Seidenspinner ◽  
Petra Zeitler ◽  
Cornelia Escher ◽  
Uwe Pleyer ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Residual Activity ◽  
Compound Heterozygous ◽  
Type I ◽  
Activity Levels ◽  
Missense Mutations ◽  
Site Mutation ◽  
Ligneous Conjunctivitis ◽  
Compound Heterozygous Mutations ◽  
Compound Heterozygotes

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 → Glu/Arg513 → His, Lys19 → Glu/Arg216 → His, and Lys19 → Glu/Leu128 → Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.

Primary Microcephaly With Anterior Predominant Pachygyria Caused by Novel Compound Heterozygous Mutations in ASPM

2015 ◽  
Vol 52 (5) ◽  
pp. e7-e8 ◽  
Author(s):  
Kazuyuki Nakamura ◽  
Takehiko Inui ◽  
Fuyuki Miya ◽  
Yonehiro Kanemura ◽  
Nobuhiko Okamoto ◽  
...  
Keyword(s):  
Compound Heterozygous ◽  
Primary Microcephaly ◽  
Compound Heterozygous Mutations

Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia

2021 ◽  
Author(s):  
Yamato Ishida ◽  
Takuya Kobayashi ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
Kazuhisa Nakayama
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Cellular Level ◽  
Compound Heterozygous ◽  
Hypomorphic Allele ◽  
Genes Encoding ◽  
Specific Proteins ◽  
Compound Heterozygous Mutations

Abstract Primary cilia contain specific proteins to achieve their functions as cellular antennae. Ciliary protein trafficking is mediated by the intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes. Mutations in genes encoding the IFT-A subunits (IFT43, IFT121/WDR35, IFT122, IFT139/TTC21B, IFT140, and IFT144/WDR19) often result in skeletal ciliopathies, including cranioectodermal dysplasia (CED). We here characterized the molecular and cellular defects of CED caused by compound heterozygous mutations in IFT144 [the missense variant IFT144(L710S) and the nonsense variant IFT144(R1103*)]. These two variants were distinct with regard to their interactions with other IFT-A subunits and with the IFT-B complex. When exogenously expressed in IFT144-knockout (KO) cells, IFT144(L710S) as well as IFT144(WT) rescued both moderately compromised ciliogenesis and the abnormal localization of ciliary proteins. As the homozygous IFT144(L710S) mutation was found to cause autosomal recessive retinitis pigmentosa, IFT144(L710S) is likely to be hypomorphic at the cellular level. In striking contrast, the exogenous expression of IFT144(R1103*) in IFT144-KO cells exacerbated the ciliogenesis defects. The expression of IFT144(R1103*) together with IFT144(WT) restored the abnormal phenotypes of IFT144-KO cells. However, the coexpression of IFT144(R1103*) with the hypomorphic IFT144(L710S) variant in IFT144-KO cells, which mimics the genotype of compound heterozygous CED patients, resulted in severe ciliogenesis defects. Taken together, these observations demonstrate that compound heterozygous mutations in IFT144 cause severe ciliary defects via a complicated mechanism, where one allele can cause severe ciliary defects when combined with a hypomorphic allele.

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