Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy

Abstract

BackgroundPhosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation.MethodsWhole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation.ResultsA novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency.ConclusionsThese results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0190-9) contains supplementary material, which is available to authorized users.

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

“…Variants in PRPS1 encoding the protein PRS‐I cause rare forms of DFNX1, CMTX5, Arts syndrome, and PRS‐I superactivity (MIM# 300661) in affected males (Gandia et al., ; Mittal, et al., ). However, recently a family with only affected females with optic atrophy, RP and neurological features overlapping CMTX5, and Arts syndrome was reported with a PRPS1 variant affecting the same codon as we report in family 1, c.46T > C, p.(Ser16Pro) (Almoguera et al., ), implicating the PRPS1 variant as the top candidate in family 1. Sanger sequencing confirmed the PRPS1 variant in the affected female proband, and its absence in unaffected siblings (1‐II:3 and 1‐II:5, Figure and Supp.…”

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

“…SH178–411 with moderate SNHL showed a lower PRS1 activity than SH178–396 with severe SNHL. A subtle discrepancy between the degree of SNHL and residual PRS1 activities in our affected siblings is not unprecedented . A previous study also reported similar results for intrafamilial phenotypic heterogeneities .…”

“…On the other hand, destabilization of the ATP‐binding site results in PRPS1 deficiency‐related disorders, encompassing the most severe forms of PRPS1 ‐deficiency syndrome, Arts syndrome, an intermediate form between CMTX5 and Arts syndrome, and CMTX5, in accordance with the residual PRS1 activities. DFNX1 mutations usually neither influence the allosteric site, nor the ATP‐binding site but, instead, induce the local protein structural changes or effect the interface of trimers . However, the structural loci of PRPS1 mutations is not always the determining factor of the types of PRPS1 ‐deficiency disorders.…”

“…A previous study showed that even an identical PRPS1 mutation of p.Gly306Glu caused both nonsyndromic and syndromic features . In females, this can originate from the skewed inactivation of mutant X‐chromosome . However, in our affected male subjects, this discrepancy between the degree of SNHL and residual PRS1 activities cannot be explained by skewed X‐chromosome inactivation.…”

“…Her PRS1 activity was significantly decreased compared to that of normal controls, although it was not as low as that of the affected male siblings (SH178–396 and SH178–411). Although most female carriers in families with PRPS1 mutations were noted to be asymptomatic, some studies reported that female carriers in families with Art syndrome occasionally exhibit a delayed onset of hearing impairment combined with ataxia and neuropathy . Tissue‐specific PRS1 expression as a result of skewed X‐chromosome inactivation and unrevealed modifiers could lead to a relatively higher PRS1 activity of the cochlear compared to that of erythrocytes in our carrier.…”