NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
National Eye Institute, National Institute of Health, Bethesda, MD, United States.
Mol Genet Metab. 2019 Feb;126(2):188-195. doi: 10.1016/j.ymgme.2018.12.001. Epub 2018 Dec 3.
CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296A > G (p.Lys99Arg) in Proband 1 and homozygous c.723G > T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.
CLN6 是一种位于内质网中的跨膜蛋白，参与溶酶体酸化。CLN6 突变导致晚发性婴儿神经元蜡样脂褐质沉积症（LINCL），以及青少年和成年发病的无视觉障碍的 NCL。在这里，我们描述了在国立卫生研究院评估的两个来自无关家庭的 LINCL 儿科患者。这两个孩子都表现出与 LINCL 相关的典型表型，只是他们没有预期的视觉障碍。全外显子组测序在 CLN6 中发现了新的双等位基因突变，即 1 号先证者的 c.218-220dupGGT（p.Trp73dup）和 c.296A>G（p.Lys99Arg），以及 2 号先证者的纯合子 c.723G>T（p.Met241Ile）。皮肤成纤维细胞的表达分析显示 CLN6 蛋白水平略有增加。这些成纤维细胞的电子显微镜图像显示除了脂褐素沉积外，还有大量的小膜结合囊泡。来自两个患者的成纤维细胞的 LysoTracker™ Red 强度增加。这项研究支持 CLN6 在溶酶体稳态中的作用，并强调了即使在视力正常的患者中，也应考虑 CLN6 突变在诊断 Batten 病中的重要性。
