Jul 2026· Human Genetics· Vol 145· 0 citations· 62 references
Medicine
TL;DR
It is demonstrated that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigated its interactions and functions, and the genotype-phenotype association for SLC26A4-related hearing loss is characterized in the context of these two isoforms.
Abstract
Pathogenic variation of SLC26A4 gene causes both Pendred syndrome (PDS) and non-syndromic enlarged vestibular aqueduct (NSEVA/DFNB4), two autosomal recessive disorders. The former accounts for approximately 6% of human genetic hearing loss, making it the second most common form of syndromic deafness after Usher syndrome, while the latter is the most common radiological malformation associated with childhood sensorineural hearing loss (SNHL). Here, we used short- and long-read single-cell RNA sequencing (scRNA-seq) of pendrin-expressing cells in the murine cochlea to identify a novel short isoform of Slc26a4. We demonstrate that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigate its interactions and functions. We also characterize the genotype-phenotype association for SLC26A4-related hearing loss in the context of these two isoforms. These results provide a new reference for molecular profiling of pendrin and offer novel insights into cell-type-specific splicing events and SLC26A4-related hearing loss.
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
Pathogenic variants in the
SLC26A4
gene (solute carrier family 26, member 4) are a common cause of inherited hearing loss. The
SLC26A4
gene encodes the transmembrane protein pendrin, a member of the SLC26 anion transporter family, with predominant expression in the inner ear, thyroid, and kidney tissues. Pathogenic
SLC26A4
variants cause nonsyndromic recessive hearing loss (DFNB4) and Pendred syndrome (sensorineural hearing loss and thyroid dysfunction). In many studies analyzing the
SLC26A4
gene, along with patients who have two recessive pathogenic
SLC26A4
variants (M2 patients) and an accurate molecular genetic diagnosis can be made, a group of patients with only one pathogenic
SLC26A4
variant (M1 patients) is often identified, which creates a diagnostic problem. The presence of M1 patients may reflect copy number variations (CNVs, deletions/duplications) in the
SLC26A4
gene that are not detected by routine diagnostic methods. The aim of the study is to search for deletions/duplications in the
SLC26A4
gene using the MLPA (Multiplex Ligation-dependent Probe Amplification) method in thirteen patients belonging to the indigenous people of the Tyva Republic (Southern Siberia), in whom only one pathogenic
SLC26A4
variant (M1 patients) was identified during the study of the etiology of hereditary hearing loss. As a result of MLPA analysis and molecular cloning in DNA samples of three M1 patients from two related Tuvinian families, a novel variant was revealed – tandem duplication of twelve nucleotides (c.1185_1196dup) in exon 10 of the
SLC26A4
gene. This variant is an in-frame insertion resulting in the inclusion of four additional amino acid residues Gly-Phe-Phe-Ser (p.(Gly396_Ser399dup)) in a highly conserved region of the pendrin protein. Most predictive programs predict the damaging effect of the c.1185_1196dup variant on the structure and function of the pendrin protein. The pathogenicity of the c.1185_1196dup variant is supported by its segregation with hearing pathology in the pedigree of patients in whom it was found in a compound heterozygous state with pathogenic
SLC26A4
variants, as well as its absence in a control sample of Tuvinians and in the world genomic databases. Functional
in vitro
studies are needed to confirm the potentially deleterious effects of the novel c.1185_1196dup (p.(Gly396_Ser399dup)) variant and its association with hearing pathology.
M. V. Zytsar, V. Danilchenko, A. Bondar et al.· Vavilov Journal of Genetics...· 0 citations
The genotypic and phenotypic spectrum of NMOAS is expanded, the pathogenic role of this variant in splicing dysregulation is confirmed, and the need for long-term monitoring of emerging comorbidities in affected patients is emphasized.
Yue Shen, Yunyu Zhou, Chao Lu et al.· Clinical Genetics· 0 citations
The first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction is reported, expanding the mutational spectrum of SLC18A2‐related disease and highlighting the importance of early genetic diagnosis.
Ali Nikkhah, R. Badv, S. Habibi et al.· Case Reports in Neurological...· 0 citations
The particular phenotype that was observed in the patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations
A family with two adult carriers of the heterozygous KCNQ2 p.(Arg214Trp) variant is reported, identified through whole-exome sequencing, including long-term follow-up into late adulthood, challenging the concept of KCNQ2 p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicating a broader phenotypic spectrum.
P. Christova, M. Ostrožovičová, J. Neupauerová et al.· BMC Neurology· 0 citations
