Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

Fischer-Zirnsak, Björn; Escande‐Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Bughaili, Mohammed Al; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Enikö K.; Choudhri, Asim F.; Krüger, Ulrike; Żemojtel, Tomasz; Ravenswaaij-Arts, Conny M. A. van; Mostafavi, Roya; Stolte‐Dijkstra, Irene; Symoens, Sofie; Pajunen, L.; Al‐Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter H.; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

doi:10.1016/j.ajhg.2015.08.001

Cited by 75 publications

(66 citation statements)

References 48 publications

(65 reference statements)

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“…Of note, in our patients, the evolution of the skeletal features seems much less severe than previously reported . Two patients presented with cataract, an uncommon finding in ARCL2A in contrast to ARCL3 caused by PYCR1 or ALDH18A1 mutations . Patient 6 had retinal detachment, unrelated to severe myopia.…”

Section: Resultscontrasting

confidence: 54%

ATP6V0A2‐related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

Beyens

Moreno‐Artero

Bodemer

et al. 2018

Experimental Dermatology

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In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa.

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Section: Resultscontrasting

confidence: 54%

ATP6V0A2‐related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

Beyens

Moreno‐Artero

Bodemer

et al. 2018

Experimental Dermatology

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“…Patients present with symptoms ranging from severe cutis laxa to adult-onset spastic paraplegia (depending on the presence of mono-or bi-allelic mutations) with concomitant hypermobility of the joints, neurodegeneration, and bilateral cataracts or corneal clouding. [66][67][68][69][70][71] These symptoms are in line with the role of proline in collagen and elastin synthesis, protein synthesis, oxidative stress defence in addition to a possible role as an inhibitory neurotransmitter. 72 Ornithine aminotransferase (OAT) converts glutamateγ-semialdehyde into ornithine coupled to glutamate transamination.…”

Section: Disorders Of Ammonia Detoxificationsupporting

confidence: 59%

Inborn errors of enzymes in glutamate metabolism

Rumping

Vringer

Houwen

et al. 2019

J of Inher Metab Disea

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Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter‐conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter‐conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however—with the exception of urea cycle defects—abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism—rather than individual glutamate and glutamine levels—the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.

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“…7). Variants in ALDH18A1 had been reported to be associated with cutis laxa III (OMIM #138250)4647, yet the patient did not present cutis laxa. Because of this inconsistent phenotype and the unknown significance of the non-synonymous variant, the variants in ALDH18A1 were not regarded as disease causing.…”

Section: Resultsmentioning

confidence: 81%

Genetic diagnosis of Mendelian disorders via RNA sequencing

et al. 2017

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Across a variety of Mendelian disorders, ∼50–75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

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Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

Cited by 75 publications

References 48 publications

ATP6V0A2‐related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

ATP6V0A2‐related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

Inborn errors of enzymes in glutamate metabolism

Genetic diagnosis of Mendelian disorders via RNA sequencing

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