Background

Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously.

Methods

Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids.

Results

Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism.

Conclusions

Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.)

中文翻译：

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黄斑疾病和周围神经病变中的丝氨酸和脂质代谢。

背景

确定具有复杂遗传模式的疾病（例如黄斑毛细血管扩张2型）的机制具有挑战性。先前已经建立了2型黄斑毛细血管扩张与丝氨酸代谢改变之间的联系。

方法

通过对患有2型黄斑毛细血管扩张的患者及其家人的外显子组序列分析，我们在SPTLC1中鉴定了一个编码丝氨酸棕榈酰转移酶（SPT）亚基的变体。因为已知影响SPT的突变会导致1型遗传性感觉神经和自主神经病（HSAN1），所以我们检查了另外10名HSAN1患者的眼科疾病。我们在患有2型黄斑毛细血管扩张但没有HSAN1或影响SPT的致病变异的患者中测定了血清氨基酸和鞘氨醇碱水平，包括脱氧鞘脂的水平。我们表征了低丝氨酸水平的小鼠，并测试了脱氧鞘脂对人类视网膜类器官的影响。

结果

确定了两个已知引起HSAN1的变体是2型黄斑毛细血管扩张的病因：11例HSAN1患者中，9名也患有2型黄斑毛细血管扩张。在没有致病性的125个2型黄斑毛细血管扩张患者中，循环脱氧鞘脂水平高84.2％在94个未受影响的对照中影响SPT的变体。脱氧鞘脂水平与丝氨酸水平呈负相关，比对照组低20.6％。小鼠中丝氨酸水平的降低导致视网膜脱氧鞘糖脂水平的增加和视觉功能受损。脱氧鞘脂在视网膜类器官中引起光感受器细胞死亡，但在脂质代谢调节剂的存在下则不会。

结论

由变体SPTLC1或SPTLC2或低水平的丝氨酸水平引起的非典型脱氧鞘糖脂水平升高是2型黄斑毛细血管扩张和周围神经病的危险因素。（由Lowy医学研究所和其他机构资助。）