Confocal Microscopy and Cellular Imaging Unit, Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.
Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.
Int J Mol Sci. 2023 Sep 5;24(18):13699. doi: 10.3390/ijms241813699.
The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of . In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient's fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of and the presence of aberrant protein aggregates in the patient's fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between variants and PCH, expanding the clinical spectrum of -related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype-phenotype correlation and the underlying mechanisms of this novel phenotype.
与神经发育状况相关的基因数量正在迅速增加。最近， 中的变体与综合征性智力障碍以及一致但仍在扩大的表型相关联。该 基因编码丝氨酸/苏氨酸蛋白磷酸酶 2A 酶的蛋白质亚基，该酶在细胞功能中发挥关键作用。我们报告了一个个体，该个体表现出桥脑小脑发育不良（PCH）、小头畸形、视神经和周围神经异常，并且缺乏癫痫和异常胼胝体等典型特征。他携带 中一个未报告的变体，位于一个非典型区域。通过使用免疫荧光和超分辨率显微镜技术进行了计算机分析、功能分析，以研究该变体的致病性。该分析涉及对患者的成纤维细胞与健康对照细胞和具有先前描述的表型的个体的细胞进行比较分析。结果表明， 表达减少，并且患者的成纤维细胞中存在异常蛋白聚集体，支持该变体的致病性。这些发现提示 变体与 PCH 之间存在潜在关联，扩大了 - 相关神经发育障碍的临床谱。需要进一步的研究和对其他患者的描述，以充分了解这种新型表型的基因型-表型相关性和潜在机制。
