Scarpato Margherita, Testa Francesco, Nesti Anna, Zeuli Roberta, Boccia Rosa, Auletta Gennaro, Banfi Sandro, Simonelli Francesca, Karali Marianthi
Medical Genetics, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy.
Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, University of Campania 'Luigi Vanvitelli', Naples, Italy.
Mol Genet Genomic Med. 2025 Feb;13(2):e70068. doi: 10.1002/mgg3.70068.
Sensorineural hearing loss (SNHL) is a frequent manifestation of syndromic inherited retinal diseases (IRDs), exemplified by the very rare form of autosomal-dominant Leber congenital amaurosis with early onset deafness (LCAEOD; OMIM #617879). LCAEOD was first described in 2017 in four families segregating heterozygous missense mutations in TUBB4B, a gene encoding a β-tubulin isotype. To date, only eight more families with similar TUBB4B-associated sensorineural disease (SND) have been reported. Most cases harbored missense variants affecting the same amino acid (Arg391) and only three families segregated variants involving different residues (Tyr310, Arg390).
We performed whole-exome sequencing and a full ophthalmological and audiological examination of the affected members in an Italian family segregating syndromic IRD with early onset deafness.
We identified a novel, ultra-rare, disease-causing variant in TUBB4B (NM_006088.6:c.1049A>C) that replaces a highly conserved lysine with threonine at amino acid position 350. The functional impact of the Lys350Thr substitution was supported by protein structure modeling studies. The variant segregates in the family members presenting retinal disease with early onset SNHL. Detailed ophthalmological assessment of the affected subjects diagnosed a progressive cone-rod dystrophy.
These findings expand the limited number of disease-causing TUBB4B variants, corroborating their association with SND forms, and suggest Lys350 is an important residue for β-tubulin function. Interestingly, our results demonstrate that TUBB4B mutations can cause cone-dominated retinal phenotypes.
感音神经性听力损失（SNHL）是综合征性遗传性视网膜疾病（IRD）的常见表现，以常染色体显性遗传的极为罕见的伴有早发性耳聋的Leber先天性黑蒙（LCAEOD；OMIM编号#617879）为例。LCAEOD于2017年首次在四个家族中被描述，这些家族中存在TUBB4B（一种编码β-微管蛋白同种型的基因）的杂合错义突变。迄今为止，仅又报道了另外八个患有类似TUBB4B相关感音神经性疾病（SND）的家族。大多数病例携带影响相同氨基酸（Arg391）的错义变体，只有三个家族分离出涉及不同残基（Tyr310、Arg390）的变体。
我们对一个患有伴有早发性耳聋的综合征性IRD的意大利家族中的患病成员进行了全外显子组测序以及全面的眼科和听力学检查。
我们在TUBB4B中鉴定出一个新的、极其罕见的致病变体（NM_006088.6:c.1049A>C），该变体在氨基酸位置350处用苏氨酸取代了一个高度保守的赖氨酸。赖氨酸350苏氨酸替代的功能影响得到了蛋白质结构建模研究的支持。该变体在患有视网膜疾病并伴有早发性SNHL的家族成员中分离。对受影响受试者的详细眼科评估诊断为进行性锥杆营养不良。
这些发现扩展了导致疾病的TUBB4B变体的有限数量，证实了它们与SND形式的关联，并表明赖氨酸350是β-微管蛋白功能的重要残基。有趣的是，我们的结果表明TUBB4B突变可导致以视锥细胞为主的视网膜表型。
