{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T18:09:25Z","timestamp":1760551765815,"version":"3.41.2"},"reference-count":24,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T00:00:00Z","timestamp":1661558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>DFNB28, a recessively inherited nonsyndromic form of deafness in humans, is caused by mutations in the <jats:italic>TRIOBP<\/jats:italic> gene (MIM #609761) on chromosome 22q13. Its protein TRIOBP helps to tightly bundle F\u2010actin filaments, forming a rootlet that penetrates through the cuticular plate into the cochlear hair cell body. Repeat motifs R1 and R2, located in exon 7 of the TRIOBP\u20105 isoform, are the actin\u2010binding domains. Deletion of both repeat motifs R1 and R2 results in complete disruption of both actin\u2010binding and bundling activities, whereas deletion of the R2 motif alone retains F\u2010actin bundling ability in stereocilia rootlets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Target sequencing, using a custom capture panel of 180 known and candidate genes associated with sensorineural hearing loss, bioinformatics processing, and data analysis were performed. Genesis 2.0 was used for variant filtering based on quality\/score read depth and minor allele frequency (MAF) thresholds of 0.005 for recessive NSHL, as reported in population\u2010based sequencing databases. All variants were reclassified based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines together with other variant interpretation guidelines for genetic hearing loss . Candidate variants were confirmed via Sanger sequencing according to standard protocols, using the ABIPRISM 3730 DNA Analyzer. DNA sequence analysis was performed with DNASTAR Lasergene software.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Candidate <jats:italic>TRIOBP<\/jats:italic> variants identified among 94 indigenous sub\u2010Saharan African individuals were characterized through segregation analysis. Family TS005 carrying variants c.572delC, p.Pro191Argfs*50, and c.3510_3513dupTGCA, p.Pro1172Cysfs*13, demonstrated perfect cosegregation with the deafness phenotype. On the other hand, variants c.505C\u2009&gt;\u2009A p.Asp168Glu and c.3636\u2009T\u2009&gt;\u2009A p.Leu1212Gln in the same family did not segregate with deafness and we have classified these variants as benign. A control family, TS067, carrying variants c.2532G\u2009&gt;\u2009T p.Leu844Arg, c.2590C\u2009&gt;\u2009A p.Asn867Lys, c.3484C\u2009&gt;\u2009T p.Pro1161Leu, and c.3621\u2009T\u2009&gt;\u2009C p.Phe1187Leu demonstrated no cosegregation allowing us to classify these variants as benign. Together with published TRIOBP variants, the results showed that genotypes combining two truncating TRIOBP variants affecting repeat motifs R1 and R2 or R2 alone lead to a deafness phenotype, while a truncating variant affecting repeat motifs R1 and R2 or R2 alone combined with a missense variant does not. Homozygous truncating variants affecting repeat motif R2 cosegregate with the deafness phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>While a single intact R1 motif may be adequate for actin\u2010binding and bundling in the stereocilia of cochlear hair cells, our findings indicate that a truncated R2 motif <jats:italic>in cis<\/jats:italic> seems to be incompatible with normal hearing, either by interfering with the function of an intact R1 motif or through another as yet unknown mechanism. Our study also suggests that most heterozygous missense variants involving exon 7 are likely to be tolerated.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2015","type":"journal-article","created":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T10:06:14Z","timestamp":1661594774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Elucidation of repeat motifs R1\u2010 and R2\u2010related <i>TRIOBP<\/i> variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5712-0498","authenticated-orcid":false,"given":"Rosemary Ida","family":"Kabahuma","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology University of Pretoria  Pretoria South Africa"},{"name":"Departments of Biochemistry, Genetics and Microbiology, Faculty of Natural and Agricultural Sciences University of Pretoria  Pretoria South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolf\u2010Dieter","family":"Schubert","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Genetics and Microbiology, Faculty of Natural and Agricultural Sciences University of Pretoria  Pretoria South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiaan","family":"Labuschagne","sequence":"additional","affiliation":[{"name":"Inqaba Biotechnology  Pretoria South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6636-2026","authenticated-orcid":false,"given":"Michael Sean","family":"Pepper","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Medicine, Department of Immunology and SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences University of Pretoria  Pretoria South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue\u2010Zhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology University of Miami Miller School of Medicine  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi400585h"},{"volume-title":"Speech perception by the hearing impaired","year":"1989","author":"Bosman A. 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