Department of Biology, Chungnam National University, Daejeon, South Korea.
The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behavior, University of Leicester, Leicester, UK.
Ann Neurol. 2024 Nov;96(5):914-931. doi: 10.1002/ana.27037. Epub 2024 Jul 29.
Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities.
Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish.
The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability.
Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914-931.
智力障碍通常是神经发育障碍的结果，其特征是智力和适应功能严重受损。X 连锁智力障碍（XLID）是这些疾病的一个子集，由 X 染色体上的遗传缺陷引起，影响大约每 1000 名男性中的 2 名。在综合征形式中，它导致广泛的认知、行为、眼部和身体残疾。
通过外显子或基因组测序，我们在 5 个无关家族的 9 名 XLID 患者中鉴定出 SRPK3 基因中的 4 个错义变体（c.475C>G；p.H159D、c.1373C>A；p.T458N 和 c.1585G>A；p.E529K、c.953C>T；p.S318L）和一个推定的截断变体（c.1413_1414del；p.Y471*）。为了验证 SRPK3 是一种新的 XLID 基因，我们在斑马鱼中建立了 SRPK3 同源物的敲除（KO）模型。
9 名经产后确诊的患者具有共同的临床特征，包括智力障碍、胼胝体发育不全、眼球运动异常和共济失调。第 9 例经产前确诊，具有复杂的结构性脑表型。这些数据共同表明 SRPK3 在神经发育障碍中的病理性作用。在受精后第 5 天的幼虫（自由游动阶段）中，KO 斑马鱼在眼球运动和鳔充气方面表现出严重缺陷，模拟了人类患者中观察到的不受控制的眼球运动和身体笨拙。在成年 KO 斑马鱼中，观察到小脑发育不全和行为异常，再现了人类小脑萎缩和智力障碍的表型。
总的来说，这些结果表明 SRPK3 在综合征性 X 连锁智力障碍的发病机制中起着至关重要的作用，并为人类和斑马鱼的大脑发育、认知和眼部功能障碍提供了新的见解。
