Dataset Information

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

ABSTRACT:

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.).

SUBMITTER: Gantner ML

PROVIDER: S-EPMC7685488 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

Gantner Marin L ML Eade Kevin K Wallace Martina M Handzlik Michal K MK Fallon Regis R Trombley Jennifer J Bonelli Roberto R Giles Sarah S Harkins-Perry Sarah S Heeren Tjebo F C TFC Sauer Lydia L Ideguchi Yoichiro Y Baldini Michelle M Scheppke Lea L Dorrell Michael I MI Kitano Maki M Hart Barbara J BJ Cai Carolyn C Nagasaki Takayuki T Badur Mehmet G MG Okada Mali M Woods Sasha M SM Egan Catherine C Gillies Mark M Guymer Robyn R Eichler Florian F Bahlo Melanie M Fruttiger Marcus M Allikmets Rando R Bernstein Paul S PS Metallo Christian M CM Friedlander Martin M

The New England journal of medicine 20190911 15

<h4>Background</h4>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.<h4>Methods</h4>Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in <i>SPTLC1</i> encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT ...[more]

PMID: 31509666

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Dataset Information

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

Background

Methods

Results

Conclusions

Publications

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

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