Missense variants in the X-linked gene<i>PRPS1</i>cause retinal degeneration in females

Fiorentino, Alessia; Fujinami, Kaoru; Arno, Gavin; Robson, Anthony G.; Pontikos, Nikolas; Armengol, Monica; Plagnol, Vincent; Hayashi, Takaaki; Iwata, Takeshi; Parker, Matthew O.; Fowler, Tom; Rendon, Augusto; Gardner, Jessica C.; Henderson, Robert H.; Cheetham, Michael E.; Webster, Andrew R.; Michaelides, Michel; Hardcastle, Alison J.

doi:10.1002/humu.23349

Cited by 27 publications

(22 citation statements)

References 46 publications

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“…It was linked to pathogenic variants c.641G>C, p.(Arg214Pro), and c.640C>T, p.(Arg214Trp). Thus, one differential diagnosis of this presentation is Usher syndrome (Fiorentino, ). As only females were affected in this cohort of five families, we may think that, when inherited in the hemizygous state in males, this could be male embryonic lethal (Fiorentino, ).…”

Section: Discussionmentioning

confidence: 99%

New PRPS1 variant p.(Met68Leu) located in the dimerization area identified in a French CMTX5 patient

Lerat

Magdelaine

Derouault

et al. 2019

Molec Gen & Gen Med

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Background CMTX5 is characterized by peripheral neuropathy, early‐onset sensorineural hearing impairment, and optic neuropathy. Only seven variants have been reported and no genotype‐phenotype correlations have yet been established. PRPS1 has a crystallographic structure, as it is composed of three dimers that constitute a hexamer. Methods Next‐generation sequencing (NGS) was performed using a custom 92‐gene panel designed for the diagnosis of Charcot‐Marie‐Tooth (CMT) and associated neuropathies. Results We report the case of a 35‐year‐old male, who had presented CMT and hearing loss since childhood associated to bilateral optic neuropathy without any sign of retinitis pigmentosa. A new hemizygous variant on chromosomic position X:106,882,604, in the PRPS1 gene, c.202A > T, p.(Met68Leu) was found. This change is predicted to lead to an altered affinity between the different subunits in the dimer, thereby may prevent the hexamer formation. Conclusion CMTX5 is probably under‐diagnosed, as an overlap among the different features due to PRPS1 exists. Patients who developed polyneuropathy associated to sensorineural deafness and optic atrophy during childhood should be assessed for PRPS1.

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Section: Discussionmentioning

confidence: 99%

New PRPS1 variant p.(Met68Leu) located in the dimerization area identified in a French CMTX5 patient

Lerat

Magdelaine

Derouault

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…86 – 88 The objective of this project was to kick-start genomic medicine in the United Kingdom by generating genome data from 100,000 individuals across rare disease and cancer to improve clinical diagnostics for patients. 89 Of note, the cost of WGS and its analyses and interpretation is far higher than for an exome. 90 But as with WES or targeted gene panel testing, exons and flanking intronic regions of genes can be screened first to identify any disease-causing variants in these regions 80 and thus, these methods are currently favoured by clinical genetics service laboratories and researchers as the first-line approach, reserving the rest of the genome for only cases unsolved by targeted screening.…”

Section: Ngsmentioning

confidence: 99%

Practical guide to genetic screening for inherited eye diseases

et al. 2020

Self Cite

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Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

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“…A similar observation was also made with PRPS1 loss-of-function mutations. Novel PRPS1 missense mutations were identified to cause retinal dystrophy in female patients, who were all heterozygous for the mutant alleles [ 28 ]. These findings also suggest that PRPS1 -associated genetic disorders may be more prevalent than previously thought.…”

Section: Prps Mutations In Neurological Disordementioning

confidence: 99%

PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome

Santos

Kwon

Moon

2020

IJMS

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While a plethora of genetic techniques have been developed over the past century, modifying specific sequences of the fruit fly genome has been a difficult, if not impossible task. clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 truly redefined molecular genetics and provided new tools to model human diseases in Drosophila melanogaster. This is particularly true for genes whose protein sequences are highly conserved. Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in nucleotide metabolism whose missense mutations are found in several neurological disorders, including Arts syndrome. In addition, PRPS is deregulated in cancer, particularly those that become resistant to cancer therapy. Notably, Drosophila PRPS shares about 90% protein sequence identity with its human orthologs, making it an ideal gene to study via CRISPR/Cas9. In this review, we will summarize recent findings on PRPS mutations in human diseases including cancer and on the molecular mechanisms by which PRPS activity is regulated. We will also discuss potential applications of Drosophila CRISPR/Cas9 to model PRPS-dependent disorders and other metabolic diseases that are associated with nucleotide metabolism.

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Missense variants in the X-linked genePRPS1cause retinal degeneration in females

Cited by 27 publications

References 46 publications

New PRPS1 variant p.(Met68Leu) located in the dimerization area identified in a French CMTX5 patient

New PRPS1 variant p.(Met68Leu) located in the dimerization area identified in a French CMTX5 patient

Practical guide to genetic screening for inherited eye diseases

PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome

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