FRMPD4, a causal gene for intellectual disability and epilepsy, is associated with X-linked non-syndromic hearing loss.
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Liedtke Daniel, Rak Kristen, Schrode Katrina M, Hehlert Philip, Chamanrou Niloofar, Bengl Daniel, Katana Radoslaw, Heydaran Soganad, Doll Julia, Han Mei, Nanda Indrajit, Senthilan Pingkalai R, Jürgens Lukas, Bieniussa Linda, Voelker Johannes, Neuner Cordula, Hofrichter Michaela Ah, Schröder Jörg, Schellens Renske T W, de Vrieze Erik, van Wijk Erwin, Zechner Ulrich, Herms Stefan, Hoffmann Per, Müller Tobias, Dittrich Marcus, Bartsch Oliver, Krawitz Peter M, Klopocki Eva, Shehata-Dieler Wafaa, Maroofian Reza, Wang Tao, Worley Paul F, Göpfert Martin C, Galehdari Hamid, Lauer Amanda M, Haaf Thomas, Vona Barbara
Аннотация
METHODS: We performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in FRMPD4. Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in Drosophila, zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in Drosophila nicht gut hörend (ngh) mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice.
RESULTS: Three affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of FRMPD4 in auditory structures. In Drosophila, quantitative analysis of sound-evoked responses in ngh mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, Frmpd4 knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype.
CONCLUSIONS: Our findings expand the phenotypic spectrum of FRMPD4 to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.