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.

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Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here, we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance (p=1.2×10 −13 ) with variants explaining ~3.2% of the affected

In vitro and in vivo studies have shown that building-associated Penicillium spores and spore extracts can induce significant inflammatory responses in lung cells and animal models of lung disease. However, because spores and spore extracts comprise mixtures of bioactive constituents often including toxins, it is impossible to resolve which constituent mediates inflammatory responses. This study examined dose-response (0.5 nM, 2.5 nM, 5.0 nM, 12.5 nM/g body weight (BW) animal) and time-course (3, 6, 24 and 48 h post instillation (PI)) relationships associated with inflammatory and cytotoxic responses in mouse lungs intratracheally instilled with pure brevianamide A, mycophenolic acid, and roquefortine C. High doses (5.0 nM and/or 12.5 nM/g BW animal) of brevianamide A and mycophenolic acid, the dominant metabolites of P. brevicompactum, and roquefortine C, the dominant metabolite of P. chrysogenum, induced significant inflammatory responses within 6 h PI, expressed as differentially elevated macrophage, neutrophil, MIP-2, TNF, and IL-6 concentrations in the bronchioalveolar lavage fluid (BALF) of intratracheally exposed mice. Macrophage and neutrophil numbers were maximal at 24 h PI; responses of the other inflammatory markers were maximal at 6 h PI. Except for macrophage numbers in mycophenolic acid-treatment animals, cells exhibited significant dose-dependent-like responses; for the chemo-/cytokine markers, dose dependency was lacking except for MIP-2 concentration in brevianamide A-treatment animals. It was also found that brevianamide A induced cytotoxicity expressed as significantly increased LDH concentration in mouse BALF, at concentrations of 12.5 nM/g BW animal and at 6 and 24 h PI. Albumin concentrations, measured as a nonspecific marker of vascular leakage, were significantly elevated in the BALF of mice treated with 12.5 nM/g nM brevianamide A/animal from 6 to 24 h PI and in > or =5.0 nM/g mycophenolic acid-treated animals at 6 to 24 h PI. These results suggest that these three toxins from Penicillium species common on damp materials in residential housing provoke compound-specific toxic responses with different toxicokinetics. Moreover, that these toxins can stimulate significant inflammatory responses in vivo might help explain some of the indoor effects associated with Penicillium spore exposures in indoor environments.