PNPT1, MYO15A, PTPRQ, and SLC12A2‐associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India

S, Paridhy Vanniya.; Chandru, Jayasankaran; Jeffrey, Justin Margret; Rabinowitz, Tom; Brownstein, Zippora; Krishnamoorthy, Mathuravalli; Avraham, Karen B.; Cheng, Lei; Shomron, Noam; Srisailapathy, C. R. Srikumari

doi:10.1111/ahg.12442

Cited by 8 publications

(7 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In previous reports, most patients with autosomal recessive inheritance also had congenital or prelingual HL [7,[36][37][38][39][40][41][42]. Three cases of autosomal recessive PTPRQ-associated HL with post-lingual HL were reported in a single previous report (exact ages unknown) [28]. Thus, we concluded that the onset age for autosomal recessive PTPRQ-associated HL will be congenital or early onset within the first decade.…”

Section: Discussionmentioning

confidence: 65%

“…Among the 17 variants identified in this study, 15 (88.2%) were loss of function variants, with the majority of variants (16/25, 64%) previously reported as also being loss of function variants [23,[28][29][30][31][32][33][34][35]. PTPRQ variants have been reported as causative for autosomal recessive and autosomal dominant HL [2].…”

Section: Discussionmentioning

confidence: 90%

“…His high frequency hearing then deteriorated from moderate to profound over 20 years, with his HL changing from flat-type to high-frequency steeply sloping HL. In previous studies, the hearing level in the patients with autosomal recessive inheritance ranged from moderate to profound [7,[28][29][30][31][32][33][34][35]. Most patients had progressive, high-frequency HL regardless of autosomal recessive or autosomal dominant inheritance [7,23,28,[37][38][39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort

Sakuma,

Nishio,

Goto

et al. 2024

Genes

View full text Add to dashboard Cite

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

show abstract

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort

Sakuma,

Nishio,

Goto

et al. 2024

Genes

View full text Add to dashboard Cite

show abstract

“…Autosomal recessive presentations have been primarily associated with Combined Oxidative Phosphorylation Deficiency Type 13 (MIM #614932) [33] and Autosomal Recessive Deafness Type 70 with or without adult-onset neurodegeneration (MIM #614934). Autosomal recessive nonsyndromic hearing impairment has been linked to compound heterozygous and homozygous variants in the PNPT1 gene [34,35]. Cystic leukoencephalopathy and early-onset hypomyelinating leukodystrophies have also been reported in association with biallelic PNPT1 variants [25,36], as well as severe multisystemic presentations of Leigh syndrome and complex neurodegenerative phenotypes, including myoclonus, choreoathetosis, cerebellar ataxia, and optic atrophy [37,38].…”

Section: Discussionmentioning

confidence: 99%

PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders

Sgobbi,

Farias,

Serrano

et al. 2024

Muscles

View full text Add to dashboard Cite

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.

show abstract

“…3D visualization was performed using Mol* Viewer in PDB (Sehnal et al, 2021). Mutai et al, 2020;Adadey et al, 2021;Koumangoye et al, 2021;Vanniya et al, 2022). The mutation 2930-2A > G has an effect on splicing leading to loss of exon 21 (Mutai et al, 2020).…”

Section: Perturbed [Cl − ] I Related Diseasesmentioning

confidence: 99%

NKCC1 and KCC2: Structural insights into phospho-regulation

Hartmann

Nothwang²

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Inhibitory neurotransmission plays a fundamental role in the central nervous system, with about 30–50% of synaptic connections being inhibitory. The action of both inhibitory neurotransmitter, gamma-aminobutyric-acid (GABA) and glycine, mainly relies on the intracellular Cl– concentration in neurons. This is set by the interplay of the cation chloride cotransporters NKCC1 (Na+, K+, Cl– cotransporter), a main Cl– uptake transporter, and KCC2 (K+, Cl– cotransporter), the principle Cl– extruder in neurons. Accordingly, their dysfunction is associated with severe neurological, psychiatric, and neurodegenerative disorders. This has triggered great interest in understanding their regulation, with a strong focus on phosphorylation. Recent structural data by cryogenic electron microscopy provide the unique possibility to gain insight into the action of these phosphorylations. Interestingly, in KCC2, six out of ten (60%) known regulatory phospho-sites reside within a region of 134 amino acid residues (12% of the total residues) between helices α8 and α9 that lacks fixed or ordered three-dimensional structures. It thus represents a so-called intrinsically disordered region. Two further phospho-sites, Tyr903 and Thr906, are also located in a disordered region between the ß8 strand and the α8 helix. We make the case that especially the disordered region between helices α8 and α9 acts as a platform to integrate different signaling pathways and simultaneously constitute a flexible, highly dynamic linker that can survey a wide variety of distinct conformations. As each conformation can have distinct binding affinities and specificity properties, this enables regulation of [Cl–]i and thus the ionic driving force in a history-dependent way. This region might thus act as a molecular processor underlying the well described phenomenon of ionic plasticity that has been ascribed to inhibitory neurotransmission. Finally, it might explain the stunning long-range effects of mutations on phospho-sites in KCC2.

show abstract

PNPT1, MYO15A, PTPRQ, and SLC12A2‐associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India

Cited by 8 publications

References 49 publications

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort

PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders

NKCC1 and KCC2: Structural insights into phospho-regulation

Contact Info

Product

Resources

About