Hearing loss occurs prior to thrombocytopenia in both mice and humans with DFNA1

DFNA1 (deafness, nonsyndromic autosomal dominant 1), initially identified as nonsyndromic sensorineural hearing loss, has been associated with an additional symptom: macrothrombocytopenia. However, the timing of the onset of hearing loss (HL) and thrombocytopenia has not been investigated, leaving it unclear which occurs earlier. Here, we generated a knock-in (KI) DFNA1 mouse model, diaphanous-related formin 1 (DIA1)^{KIΔv3/KIΔv3}, in which Aequorea coerulescens green fluorescent protein (AcGFP)-tagged human DIA1(p.R1213X) was knocked into the ATG site of Dia1. Additionally, the exon 7 of Dia1 was deleted using genome editing to knock out (KO) Dia1-v3, a specific variant of Dia1. AcGFP-DIA1(p.R1213X) expression and endogenous DIA1 KO were confirmed in cochleae and platelets. Hearing function in DIA1^{KIΔv3/KIΔv3}, but not DIA1^KIΔv3/+ mice, evaluated by auditory brainstem response, was significantly worse at low frequencies compared to wild-type (WT) mice starting at 3 months of age (3M), with progressive deterioration. Using confocal microscopy and scanning electron microscopy, various stereociliary deformities were identified in the cochleae of DIA1^{KIΔv3/KIΔv3} mice. Platelet counts in DIA1^{KIΔv3/KIΔv3}, but not DIA1^KIΔv3/+ mice, were significantly lower than those in WT mice at 12M, but not at 6M. Furthermore, in a cohort of eight patients with DFNA1 harboring the p.R1213X mutation, HL preceded thrombocytopenia in three individuals. Thus, in both mice and humans, though HL and thrombocytopenia are progressive, HL manifests earlier than thrombocytopenia. Unlike myosin heavy chain 9 (MYH9)-related diseases, thrombocytopenia cannot be a predictive marker for HL in DFNA1. Nevertheless, monitoring platelet counts could provide insights into the progression of the hearing impairments in patients with DFNA1.