High prevalence of CDH23 with congenital high-frequ ri i 6, K er on d membrane domain (exon 65), and a cytoplasmic domain ation. CDH23 homodimers interact in trans with
Mizutari et al. Orphanet Journal of Rare Diseases (2015) 10:60
DOI 10.1186/s13023-015-0276-zally, with the Japanese population having a uniqueHigashigaoka, Meguro-ku, Tokyo 152-8902, Japan
Full list of author information is available at the end of the article(exons 66–70). Among the 113 human cadherin superfamily members, CDH23 is one of 11 that are solely responsible for hereditary diseases . CDH23 is expressed in the outer and inner hair cells. The stereociliary expression of CDH23 in inner ear hair cells exhibits two patterns. One is transient expression during
PCDH15 homodimers to form filaments, and they play a key role in the mechanoelectrical transduction channel at the top of the lower stereocilia [3-5].
Mutations in CDH23 are responsible for both Usher syndrome 1D (USH1D: OMIM #601067) [6-9] and autosomal recessive non-syndromic hearing loss (DFNB12:
OMIM #601386) [10-12]. Individuals with USH1D usually carry a truncated CDH23 protein because of nonsense, frameshift, or splice-site mutations, whereas those with DFNB12 usually carry missense mutations in any domain [7,10,13]. The mutation spectrums differ region* Correspondence: firstname.lastname@example.org 1Laboratory of Auditory Disorders, National Institute of Sensory Organs,
National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan 8Medical Genetics Center, National Tokyo Medical Center, 2-5-1herin repeat domains (exons 2–64), a single-pass trans-subjects for CDH23 mutation analysis were selected according to the following criteria: 1) Sporadic or recessively inherited hearing loss 2) bilateral non-syndromic congenital hearing loss, 3) no cochlear malformation, 4) a poorer hearing level at high frequencies than at low frequencies, and 5) severe or profound hearing loss at higher frequencies.
Results: Seventy-two subjects were selected from 621 consecutive probands who did not have environmental causes for their hearing loss. After direct sequencing, 13 of the 72 probands (18.1%) had homozygous or compound heterozygous CDH23 mutations. In total, we identified 16 CDH23 mutations, including five novel mutations. The 16 mutations included 12 missense, two frameshift, and two splice-site mutations.
Conclusions: These results revealed that CDH23 mutations are highly prevalent in patients with congenital high-frequency sporadic or recessively inherited hearing loss and that the mutation spectrum was diverse, indicating that patients with these clinical features merit genetic analysis.
Keywords: CDH23, Congenital hearing loss, DFNB12, Gene mutation, Phenotype
CDH23, located on chromosome 10, contains 70 exons and encodes a predicted 3354 amino acid protein. The untranslated region is followed by 27 extracellular cadthe development of hair bundles with procadherin 15 (PCDH15) and CDH23 forming side links and kinociliary links at their N-termini . The second pattern is stable expression in tip links at the top of stereocilia from the developmental stage onwards until ear matur-recessively inherited hea
Kunio Mizutari1,2, Hideki Mutai1, Kazunori Namba1, Yuko M
Sawako Masuda4, Noriko Morimoto5, Hirokazu Sakamoto
Background: Mutations in CDH23 are responsible for Ush
In this study, we revealed the prevalence of CDH23 mutati
Methods: After excluding patients with GJB2 mutations an© 2015 Mizutari et al.Open Access mutations in patients ency sporadic or ng loss yanaga1, Atsuko Nakano3, Yukiko Arimoto3, imitaka Kaga7 and Tatsuo Matsunaga1,8* syndrome 1D and recessive non-syndromic hearing loss. s among patients with specific clinical characteristics. mitochondrial m.1555A > G and m.3243A > G mutations,
Mizutari et al. Orphanet Journal of Rare Diseases (2015) 10:60 Page 2 of 9mutation spectrum [12,14]. Recently, it was reported that 3.7% of recessive inherited hearing loss cases in the
Japanese population involve homozygous or heterozygous CDH23 mutations .
In this study, we analyzed CDH23 in a Japanese population that was selected on the basis of DFNB12 and
USH1D clinical features [12,14-16] after excluding patients with GJB2 mutations and mitochondrial m.1555A >G and m.3243A >G mutations. We identified an extremely high prevalence of CDH23 mutations in this population, and our findings expanded the CDH23 mutation spectrum, including five novel mutations.
All participating subjects, or their parents if the subjects were less than 20 years old, provided informed consent.
The project was approved by the institutional review board of each institute. The patients were collected from the 11 institutes listed below: National Tokyo Medical
Center, Chiba Children’s Hospital, National Mie Hospital,
National Center for Child Health and Development, Hyogo
Prefectural Kobe Children’s Hospital, Keio University
School of Medicine, National Hospital Organization
Kanazawa Medical Center, Kanagawa Children’s Medical
Center, National Hospital Organization Sendai Medical
Center, Kanto Rosai Hospital, and Hiroshima Prefectural
Hospital. All investigations were conducted according to the principles expressed in the Declaration of Helsinki.
For the analysis of CDH23 mutations, we selected subjects who did not have hearing loss owing to environmental causes and who had participated in a genetic study at our institutes, with each subject meeting the following criteria: 1) sporadic or recessively inherited hearing loss; 2) bilateral non-syndromic congenital hearing loss; 3) a lack of cochlear malformations among those who underwent a computed tomography scan and/or magnetic resonance imaging; 4) a poorer hearing level at high frequencies (e.g., 2 kHz, 4 kHz) than at low frequencies (e.g., 250 kHz, 500 Hz); and 5) severe or profound hearing loss over 70 dB at frequencies exceeding 2 kHz. These clinical features were based on the reported phenotypes of DFNB12 and USH1D [12,14-16].