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Genet."],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing.\n                    <jats:italic>PKHD1L1<\/jats:italic>\n                    was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in\n                    <jats:italic>PKHD1L1<\/jats:italic>\n                    also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in\n                    <jats:italic>PKHD1L1<\/jats:italic>\n                    that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G&gt;A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate\n                    <jats:italic>PKHD1L1<\/jats:italic>\n                    with nonsyndromic mild\u2013moderate to severe sensorineural hearing loss.\n                    <jats:italic>PKHD1L1<\/jats:italic>\n                    testing in individuals with mild\u2013moderate hearing loss may identify further affected families.\n                  <\/jats:p>","DOI":"10.1007\/s00439-024-02649-2","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T19:01:43Z","timestamp":1709924503000},"page":"311-329","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss"],"prefix":"10.1007","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3485-6654","authenticated-orcid":false,"given":"Shelby E.","family":"Redfield","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-3345","authenticated-orcid":false,"given":"Pedro","family":"De-la-Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3787","authenticated-orcid":false,"given":"Mina","family":"Zamani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hina","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gholamreza","family":"Shariati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Karimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0851-9272","authenticated-orcid":false,"given":"Margaret A.","family":"Kenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go Hun","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1912-0235","authenticated-orcid":false,"given":"Sadaf","family":"Naz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Galehdari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2076-6818","authenticated-orcid":false,"given":"Artur A.","family":"Indzhykulian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5324-4805","authenticated-orcid":false,"given":"A. 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The other authors have no conflicts to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Written informed consent was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Consent to publish was obtained from all participants.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"This study was approved by the institutional review boards of Boston Children\u2019s Hospital (IRB P-00031494), University Medical Center G\u00f6ttingen (No. 3\/2\/16), and the School of Biological Sciences, University of Punjab, Lahore, Pakistan (IRB No. 00005281).","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}