Whole Exome Sequencing Reveals a XPNPEP3 Novel Mutation Causing Nephronophthisis in a Pediatric Patient

Alizadeh, Rasoul; Jamshidi, Sanaz; Keramatipour, Mohammad; Moeinian, Parisa; Hosseini, Rozita; Otukesh, H; Talebi, Saeed

doi:10.29252/ibj.24.6.400

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…The rate of kidney failure was also slower in this case compared with previously reported who had an early need for dialysis. 2 , 3 Taken together, our findings expand the spectrum of disorders associated with variants in XPNPEP3 (eTable 1, links.lww.com/NXG/A635 ) . Early onset, intellectual disability, and cardiomyopathy were additional features in 2 Turkish siblings harboring a frame shift variant in XPNPEP3 and deficits in CI.…”

Section: Discussionsupporting

confidence: 68%

“…O'Toole et al 2 reported 2 families (5 patients) featuring nephronophthisis and variable neurologic signs, whereas isolated early-onset nephronophthisis was reported once. 3 Associated symptoms include tremor, sensorineural hearing loss, seizures, intellectual disability (ID), cardiomyopathy, and pancreatic cysts. 2 We report a man presenting with ataxia, hearing loss, myopathy, and chronic kidney failure associated with a novel homozygous truncating variant in XPNPEP3 .…”

Section: Introductionmentioning

confidence: 99%

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Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3

Ben-Shabat,

Kvarnung,

Sperker

et al. 2023

Neurol Genet

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Objectives Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3 . Methods Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed. Results Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in XPNPEP3 . A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts. Discussion This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in XPNPEP3 . Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of XPNPEP3 -related diseases.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3

Ben-Shabat,

Kvarnung,

Sperker

et al. 2023

Neurol Genet

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“…Genes linked to NPHP encode components of cilia [ 92 ]. Pathogenic variants in XPNPEP3 , encoding a mitochondrial protease, have been identified in NPHPL1 (nephronophthisis-like neuropathy 1), which closely resembles NPHP [ 93 , 94 , 95 ]. While XPNPEP3 is believed to be implicated in the processing of cilia proteins, it does not localize to cilia, as do proteins involved in NPHP [ 94 ].…”

Section: Genes Linked To Mitochondrial Protein Processing and Cardiom...mentioning

confidence: 99%

Mitochondrial Protein Homeostasis and Cardiomyopathy

Wachoski-Dark

Zhao

Khan

et al. 2022

IJMS

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Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics.

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“…A second study identified two new variants (1357G>T and c.931_934 delAACA) in different probands, all of them presenting with different grades of autosomal recessive nephronophthisis [ 82 ]. Finally, a recent study identify a new homozygous variant in the XPNPEP3 gene (p.Q241Tfs*13) associated with a paediatric nephronophthisis [ 83 ]. ( Table 1 ).…”

Section: Defects In Presequence Dependent Importmentioning

confidence: 99%

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

Ruiz‐Pesini

Montoya

Pacheu-Grau

2021

Genes

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In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases.

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Whole Exome Sequencing Reveals a XPNPEP3 Novel Mutation Causing Nephronophthisis in a Pediatric Patient

Cited by 5 publications

References 17 publications

Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3

Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3

Mitochondrial Protein Homeostasis and Cardiomyopathy

Molecular Insights into Mitochondrial Protein Translocation and Human Disease

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