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- Prasad, Sonal, 1988-, et al.
(author)
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Radixin modulates the function of outer hair cell stereocilia
- 2020
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In: Communications Biology. - : Nature Research. - 2399-3642. ; 3:1
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Journal article (peer-reviewed)abstract
- The stereocilia of the inner ear sensory cells contain the actin-binding protein radixin, encoded by RDX. Radixin is important for hearing but remains functionally obscure. To determine how radixin influences hearing sensitivity, we used a custom rapid imaging technique to visualize stereocilia motion while measuring electrical potential amplitudes during acoustic stimulation. Radixin inhibition decreased sound-evoked electrical potentials. Other functional measures, including electrically induced sensory cell motility and sound-evoked stereocilia deflections, showed a minor amplitude increase. These unique functional alterations demonstrate radixin as necessary for conversion of sound into electrical signals at acoustic rates. We identified patients with RDX variants with normal hearing at birth who showed rapidly deteriorating hearing during the first months of life. This may be overlooked by newborn hearing screening and explained by multiple disturbances in postnatal sensory cells. We conclude radixin is necessary for ensuring normal conversion of sound to electrical signals in the inner ear.
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| 2. |
- Rad, Aboulfazl, et al.
(author)
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Expanding the spectrum of phenotypes for MPDZ: Report of four unrelated families and review of the literature
- 2024
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In: CLINICAL GENETICS. - 0009-9163 .- 1399-0004.
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Journal article (peer-reviewed)abstract
- MPDZ, a gene with diverse functions mediating cell-cell junction interactions, receptor signaling, and binding multivalent scaffold proteins, is associated with a spectrum of clinically heterogeneous phenotypes with biallelic perturbation. Despite its clinical relevance, the mechanistic underpinnings of these variants remain elusive, underscoring the need for extensive case series and functional investigations. In this study, we conducted a systematic review of cases in the literature through two electronic databases following the PRISMA guidelines. We selected nine studies, including 18 patients, with homozygous or compound heterozygous variants in MPDZ and added five patients from four unrelated families with novel MPDZ variants. To evaluate the role of Mpdz on hearing, we analyzed available auditory electrophysiology data from a knockout murine model (Mpdz(em1(IMPC)J/em1(IMPC)J)) generated by the International Mouse Phenotyping Consortium. Using exome and genome sequencing, we identified three families with compound heterozygous variants, and one family with a homozygous frameshift variant. MPDZ-related disease is clinically heterogenous with hydrocephaly, vision impairment, hearing impairment and cardiovascular disease occurring most frequently. Additionally, we describe two unrelated patients with spasticity, expanding the phenotypic spectrum. Our murine analysis of the Mpdz(em1(IMPC)J/em1(IMPC)J) allele showed severe hearing impairment. Overall, we expand understanding of MPDZ-related phenotypes and highlight hearing impairment and spasticity among the heterogeneous phenotypes.
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| 3. |
- Saadi, Saadia Maryam, et al.
(author)
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Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders
- 2023
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In: Genes. - : MDPI AG. - 2073-4425. ; 14:7
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Journal article (peer-reviewed)abstract
- Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.
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| 4. |
- Tranebjærg, Lisbeth, et al.
(author)
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The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management
- 2018
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In: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 137:2, s. 111-127
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Journal article (peer-reviewed)abstract
- Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.
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