Paris Cité University, INSERM UMR1163, Imagine Institute, 75015 Paris, France.
Pediatric Neurology Unit, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, 31008 Pamplona, Spain.
Brain. 2022 Oct 21;145(10):3711-3722. doi: 10.1093/brain/awac110.
Sulphated proteoglycans are essential in skeletal and brain development. Recently, pathogenic variants in genes encoding proteins involved in the proteoglycan biosynthesis have been identified in a range of chondrodysplasia associated with intellectual disability. Nevertheless, several patients remain with unidentified molecular basis. This study aimed to contribute to the deciphering of new molecular bases in patients with chondrodysplasia and neurodevelopmental disease. Exome sequencing was performed to identify pathogenic variants in patients presenting with chondrodysplasia and intellectual disability. The pathogenic effects of the potentially causative variants were analysed by functional studies. We identified homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2 in two patients with pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. By functional analyses, we showed that the variants affect SLC35B2 mRNA expression and protein subcellular localization leading to a functional impairment of the protein. Consistent with those results, we detected proteoglycan sulphation impairment in SLC35B2 patient fibroblasts and serum. Our data support that SLC35B2 functional impairment causes a novel syndromic chondrodysplasia with hypomyelinating leukodystrophy, most likely through a proteoglycan sulphation defect. This is the first time that SLC35B2 variants are associated with bone and brain development in human.
硫酸化蛋白聚糖对于骨骼和大脑发育至关重要。最近，在与智力障碍相关的一系列软骨发育不全中，已鉴定出编码参与蛋白聚糖生物合成的蛋白的基因中的致病性变异。然而，仍有一些患者的分子基础未被识别。本研究旨在为软骨发育不全和神经发育疾病患者的新分子基础的破译做出贡献。对存在软骨发育不全和智力障碍的患者进行外显子组测序，以鉴定致病性变异。通过功能研究分析潜在致病变异的致病效应。我们在两名存在产前和产后生长迟缓、脊柱侧凸、严重运动和智力残疾以及脱髓鞘性白质营养不良的患者中发现了 SLC35B2 中的纯合变异（c.1218_1220del 和 c.1224_1225del）。通过功能分析，我们表明这些变异会影响 SLC35B2 mRNA 表达和蛋白亚细胞定位，从而导致蛋白功能受损。与这些结果一致，我们在 SLC35B2 患者的成纤维细胞和血清中检测到蛋白聚糖硫酸化受损。我们的数据支持 SLC35B2 功能受损导致一种新型伴有脱髓鞘性白质营养不良的综合征性软骨发育不全，很可能是通过蛋白聚糖硫酸化缺陷引起的。这是首次在人类中发现 SLC35B2 变异与骨骼和大脑发育有关。
