Functional characterization of a novel loss-of-function mutation of <i>PRPS1</i>
 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention

Kim, So Young; Kim, Ah Reum; Kim, Nayoung K.D.; Lee, Chung; Han, Jin Hee; Kim, Min Young; Jeon, Eun Hee; Park, Woong-Yang; Mittal, Rahul; Yan, Denise; Liu, Xue Zhong; Choi, Byung Yoon

doi:10.1002/jgm.2935

Cited by 10 publications

(15 citation statements)

References 31 publications

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“…All 18 patients had congenital/early-onset SNHL, ID, muscular hypotonia, and muscle weakness, 17 had visual impairment, 16 had ataxia, 15 showed DD, 14 showed susceptibility to infections, 12 died in early childhood, four developed peripheral neuropathy, three presented with muscle weakness exacerbation after infections, two had seizures, and one developed behavioral disturbances. In addition, 10 male patients from four families with the classical symptom triad of CMTX5 (early-onset SNHL, peripheral neuropathy, and optic atrophy) [ [19] , [20] , [21] ], another 10 male patients from four families with only SNHL and peripheral neuropathy [ [22] , [23] , [24] ], and 36 male patients from eight families with DFN2 [ 23 , [25] , [26] , [27] , [28] ] with variants in the PRPS1 gene have been reported. Intrafamilial phenotypic variation was described in a Spanish family with nine affected males—all presented with prelingual severe-to-profound SNHL, but three males had additional features (global DD, mild ID, seizures, and clubfoot) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene

Puusepp

Reinson

Pajusalu

et al. 2020

Molecular Genetics and Metabolism Reports

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The PRPS1 gene, located on Xq22.3, encodes phosphoribosyl-pyrophosphate synthetase (PRPS), a key enzyme in de novo purine synthesis. Three clinical phenotypes are associated with loss-of-function PRPS1 variants and decreased PRPS activity: Arts syndrome (OMIM: 301835 ), Charcot–Marie–Tooth disease type 5 (CMTX5, OMIM: 311070 ), and nonsyndromic X-linked deafness (DFN2, OMIM: 304500 ). Hearing loss is present in all cases. CMTX5 patients also show peripheral neuropathy and optic atrophy. Arts syndrome includes developmental delay, intellectual disability, ataxia, and susceptibility to infections, in addition to the above three features. Gain-of-function PRPS1 variants result in PRPS superactivity (OMIM: 300661 ) with hyperuricemia and gout. We report a 6-year-old boy who presented with marked generalized muscular hypotonia, global developmental delay, lack of speech, trunk instability, exercise intolerance, hypomimic face with open mouth, oropharyngeal dysphagia, dysarthria, and frequent upper respiratory tract infections. However, his nerve conduction velocity, audiologic, and funduscopic investigations were normal. A novel hemizygous variant, c.130A > G p.(Ile44Val), was found in the PRPS1 gene by panel sequencing. PRPS activity in erythrocytes was markedly reduced, confirming the pathogenicity of the variant. Serum uric acid and urinary purine and pyrimidine metabolite levels were normal. In conclusion, we present a novel PRPS1 loss-of-function variant in a patient with some clinical features of Arts syndrome, but lacking a major attribute, hearing loss, which is congenital/early-onset in all other reported Arts syndrome patients. In addition, it is important to acknowledge that normal levels of serum and urinary purine and pyrimidine metabolites do not exclude PRPS1 -related disorders.

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Section: Discussionmentioning

confidence: 99%

Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene

Puusepp

Reinson

Pajusalu

et al. 2020

Molecular Genetics and Metabolism Reports

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“…Most patients in the four families with DFNX1/DFN2 have postlingual progressive nonsyndromic hearing loss, though congenital profound nonsyndromic hearing loss was also reported in one family (Tyson et al, ; Manolis et al, ; Cui et al, ; Petersen et al, ; Liu et al, ; Liu et al, ; Kim et al, ). Among seven exons of PRPS1 encoding PRS‐I of 318 amino acids, four missense mutations of PRPS1 occur in both exon 2 (c.G193A, p.D65N; c.G259A, p.A87T) and exon 7 (c.T869C, p.I290T; c.G916A, p.G306R) (Liu et al, ).…”

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confidence: 98%

Zebrafish Model for Nonsyndromic X‐Linked Sensorineural Deafness, DFNX1

DeSmidt

Zou

Grati

et al. 2019

The Anatomical Record

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Hereditary deafness is often a neurosensory disorder and affects the quality of life of humans. Only three X‐linked genes (POU class 3 homeobox 4 (POU3F4), phosphoribosyl pyrophosphate synthetase 1 (PRPS1), and small muscle protein X‐linked (SMPX)) are known to be involved in nonsyndromic hearing loss. Four PRPS1 missense mutations have been found to associate with X‐linked nonsyndromic sensorineural deafness (DFNX1/DFN2) in humans. However, a causative relationship between PRPS1 mutations and hearing loss in humans has not been well studied in any animal model. Phosphoribosyl pyrophosphate synthetase 1 (PRS‐I) is highly conserved in vertebrate taxa. In this study, we used the zebrafish as a model to investigate the auditory role of zebrafish orthologs (prps1a and prps1b) of the human PRPS1 gene with whole mount in situ hybridization, reverse transcription polymerase chain reaction, phenotypic screening, confocal imaging, and electrophysiological methods. We found that both prps1a and prps1b genes were expressed in the inner ear of zebrafish. Splice‐blocking antisense morpholino oligonucleotides (MO1 and MO2) caused exon‐2 skip and intron‐2 retention of prps1a and exon‐2 skip and intron‐1 retention of prps1b to knock down functions of the genes, respectively. MO1 and MO2 morphants had smaller otic vesicles and otoliths, fewer inner ear hair cells, and lower microphonic response amplitude and sensitivity than control zebrafish. Therefore, knockdown of either prps1a or prps1b resulted in significant sensorineural hearing loss in zebrafish. We conclude that the prps1 genes are essential for hearing in zebrafish, which has the potential to help us understand the biology of human deafness DFNX1/DFN2. Anat Rec, 303:544–555, 2020. © 2019 American Association for Anatomy

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“…Although most female carriers in families with PRPS1 variants were noted to be asymptomatic (Kim et al, 2007), some studies report that female carriers in families with Arts syndrome or CMTX5 occasionally exhibit delayed onset hearing impairment, sometimes combined with ataxia and neuropathy (Almoguera et al, 2014;Arts, Loonen, Sengers, & Slooff, 1993;de Brouwer et al, 2010;Kim et al, 2016;Liu et al, 2010;Synofzik et al, 2014). In addition, a missense variant, p.Ser16Pro, has been reported in affected females in one family as the cause of optic atrophy, RP and neurological features overlapping CMTX5, and Arts syndrome, with no affected males (Almoguera et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Fiorentino¹,

Fujinami²,

Arno³

et al. 2017

Human Mutation

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Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1

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Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention

Cited by 10 publications

References 31 publications

Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene

Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene

Zebrafish Model for Nonsyndromic X‐Linked Sensorineural Deafness, DFNX1

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

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