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Clinical and Molecular Characterization of POU3F4

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Clinical and Molecular Characterization of POU3F4 Su et al. BMC Medical Genetics (2018) 19:157 https://doi.org/10.1186/s12881-018-0630-9 RESEARCH ARTICLE Open Access Clinical and molecular characterization of POU3F4 mutations in multiple DFNX2 Chinese families Yu Su1,2†, Xue Gao1,4†, Sha-Sha Huang1†, Jing-Ning Mao3, Bang-Qing Huang2, Jian-Dong Zhao1, Dong-Yang Kang1, Xin Zhang1 and Pu Dai1* Abstract Background: Many X-linked non-syndromic hearing loss (HL) cases are caused by various mutations in the POU domain class 3 transcription factor 4 (POU3F4) gene. This study aimed to identify allelic variants of this gene in two Chinese families displaying X-linked inheritance deafness-2 (DFNX2) and one sporadic case with indefinite inheritance pattern. Methods: Direct DNA sequencing of the POU3F4 gene was performed in these families and in 100 Chinese individuals with normal hearing. Results: There are characteristic imaging findings in DFNX2 Chinese families with POU3F4 mutations. The temporal bone computed tomography (CT) images of patients with DFNX2 are characterized by a thickened stapes footplate, hypoplasia of the cochlear base, absence of the bony modiolus, and dilated internal acoustic meatus (IAM) as well as by abnormally wide communication between the IAM and the basal turn of the cochlea. We identified three causative mutations in POU3F4 for three probands and their extended families. In family 1468, we observed a novel deletion mutation, c.973delT, which is predicted to result in a p.Trp325Gly amino acid frameshift. In family 2741, the mutation c. 927delCTC was identified, which is predicted to result in the deletion of serine at position 310. In both families, the mutations were located in the POU homeodomain and are predicted to truncate the C-terminus of the POU domain. In the third family, a novel de novo transversion mutation (c.669 T > A) was identified in a 5-year-old boy that resulted in a nonsense mutation (p.Tyr223*). The mutation created a new stop codon and is predicted to result in a truncated POU3F4 protein. Conclusions: Based on characteristic radiological findings and clinical features, POU3F4 gene mutation analysis will increase the success rate of stapes operations and cochlear implantations, and improve molecular diagnosis, genetic counseling, and knowledge of the molecular epidemiology of HL among patients with DFNX2. Keywords: POU3F4, DFNX2, X-linked deafness, Mutation Background of cases and with autosomal dominant transmission in Hearing loss (HL) affects 1–3 per 1000 newborns, and 15–20% of cases; 2–3% of human hereditary HL is the majority of congenital cases of HL are attributable to caused by X-linked mutations [2, 3].To date, six deafness genetic factors [1]. Previous studies have indicated that loci (DFNX1–6) have been mapped to chromosome X, deafness is transmitted with an inheritance pattern con- with five of the corresponding genes identified: PRPS1 sistent with autosomal recessive transmission in 75–77% for DFNX1 [4], POU3F4 for DFNX2 [5], SMPX for DFNX4, AIFM1 for DFNX5 [6] and COL4A6 for DFNX6 [7–9].PRPS1 on Xq22 encodes phosphoribosyl pyro- * Correspondence: [email protected] † phosphate synthetase 1; POU3F4 on Xq21 encodes a Yu Su, Xue Gao and Sha-Sha Huang contributed equally to this work. 1Department of Otorhinolaryngology, Head and Neck Surgery, PLA General member of a transcription factor family that contains a Hospital, Beijing 100853, People’s Republic of China POU domain; SMPX on Xp22 encodes the small muscle Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Su et al. BMC Medical Genetics (2018) 19:157 Page 2 of 10 protein; and the recently identified gene COL4A6 en- according to the protocol provided by the manufacturer codes the alpha-6 chain of collagen type IV at Xp21. (Tiangen Biotech, Beijing, China). DFNX2, X-linked deafness type 2, is the most common type of X-linked HL in humans. Mutations in the Families 1486, 2741, and ZSJ POU3F4 gene were first found in 1995 [5] following its Family 1486 is a four-generation Chinese family, and the chromosomal localization to the X chromosome in 1988 pedigree of this family is consistent with an X-linked in- [10]. In fact, deafness caused by POU3F4 mutation ac- heritance pattern (Fig. 1b). Fifteen family members, in- counts for nearly 50% of all cases of X-linked cluding four patients (4 males: II:1, II:2, IV:3, and IV:4) non-syndromic HL [5, 11]. Clinical features of DFNX2 with HL and 11 individuals (5 males: II:5, III:1, III:4, often include mixed, progressive HL, temporal bone III:6, and IV:1, and 6 females: II:4, III:3, III:5, IV:2, IV:5, anomalies, and stapes fixation [12, 13]. Affected males and IV:6) with normal hearing participated. The medical exhibit either mixed deafness or, less commonly, only histories of the participants were obtained through sensorineural deafness. The temporal bone computed structured questionnaires, otological examinations, and tomography (CT) image is characterized by a thick- systematic assessments for signs of syndromic deafness. ened stapes footplate, hypoplasia of the cochlear base, The proband underwent temporal bone CT scans and absence of the bony modiolus, and dilated internal auditory brainstem responses. Pure tone audiometry was acoustic meatus (IAM), as well as abnormally wide not available for the proband because of his young age. communication between the IAM and the basal turn of Family 2741 is also a four-generation Chinese family, the cochlea [14]. Nance et al. first reported X-linked and the pedigree of this family showed a typical X-linked mixed deafness with congenital stapes fixation and a recessive inheritance pattern of HL (Fig. 2a). Ten family perilymphatic gusher [15]. Sennaroglu et al. suggested members were assessed: three patients (three males: II:3, that the radiologic phenotype “X-linked deafness with III:9, and IV:2) with HL and seven individuals (two stapes gusher” be called “incomplete partition type males: II:6 and III:13, and five females: II:5, II:7, II:12, III” (IP- III) [16]. III:10, and III:12) with normal hearing. The medical his- To date, nearly 60 different mutations in the coding tories of the participants were obtained through struc- region of the POU3F4 gene, including deletions, inver- tured questionnaires, otological examinations, and sions, and duplications, have been reported to be associ- systematic assessments for signs of syndromic deafness. ated with non-syndromic HL in families with DFNX2 We obtained 10 blood samples (II:3, II:5, II:7, II:6, II:12, (Table 1). Several reports have described mutations of III:9, III:10, III:12, III:14, and IV:2) and the affected boy POU3F4 in patients with HL and temporal bone abnor- (IV:2) and his uncle (III:9) underwent temporal bone CT malities. In this report, we describe the clinical features scans. Due to long distances, no temporal bone CT and genetic analysis of two Chinese families displaying image was obtained from the affected boy’s granduncle X-linked inheritance HL and one sporadic case with (II:3). The proband presented with mixed HL, his uncle indefinite inheritance pattern. Moreover, two novel had profound sensorineural HL, and the females pre- mutations (including a de novo mutation) were identi- sented with normal hearing. fied in the POU-specific and homeodomains of POU3F4, In family ZSJ, the proband was a 5-year-old boy with coinciding with familial HL. congenital inner ear malformation and profound HL, but no one else in his family had HL, the inheritance Methods pattern is unclear (Fig. 3e). Because of minimal progres- Clinical evaluation sion in auditory ability after wearing hearing aid for Patients were enrolled from families 1486, 2741, and ZSJ 3 years and profound HL, the boy underwent coch- (three ethnic Han Chinese families) through the Depart- lear implant surgery on his left ear at Chinese PLA ment of Otolaryngology of the General Hospital of the General Hospital. A physical and otoscopic examin- People’s Liberation Army, Beijing, China which collected ation, temporal bone CT scans, and audiological data and DNA samples from more than 10,000 patients. studies were performed before surgery. According to We chose three families with specific manifestation of the radiological and hearing findings, we suspected temporal bone CT from this cohort. Clinical evaluations, that he had DFNX2, and a mutation analysis of the temporal bone imaging results, audiograms, and other POU3F4 gene was performed. relevant clinical information were collected for each family member. The probands had no obvious syn- Sequencing analysis of POU3F4 dromic symptoms, and GJB2, SLC26A4, and m.1555A > Genomic DNA was extracted from blood using a DNA G and m.1494C > T mutations in mtDNA 12S rRNA Extraction Kit (Tiangen Biotech). Briefly, the entire cod- were excluded. Genomic DNA was extracted from ing region and splice sites of the single exon of POU3F4 peripheral blood using a blood DNA extraction kit (NM_000307.1) were amplified in three
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