ABSTRACT
Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.
ABSTRACT
BACKGROUND: HIV and highly active antiretroviral therapies have been associated with changes in individuals' lipid profiles and fat distribution (lipodystrophy). A pilot study was conducted for a randomised controlled trial to evaluate whether lipodystrophy in HIV patients can be controlled by adopting the low-fat and low-cholesterol diet or the modified Mediterranean diet. METHODS: Forty-eight HIV patients were randomised into two diet groups. Thirty-six (75%) completed the 1-year pilot study with regular dietetic consultations, during which time lipid levels, weight, body mass index and fat distribution were recorded. Differences between and within groups were determined. RESULTS: Undesirable body fat changes in the low-fat diet group included decreases in tricep skinfold (from 19.9 mm to 15.4 mm (P = 0.03)), hip circumference (from 93.6 cm to 91.7 cm (P = 0.01)) but a significant increase in waist-to-hip ratio (from 0.87 to 0.89 (P = 0.003)). Serum cholesterol increased significantly in the Mediterranean diet group at 9 and 12 months (from 4.6 to 5.06 mmol L(-1) (P = 0.03) and 5.12 mmol L(-1) (P = 0.01)) with no obvious change in the low-fat diet group. Serum triglyceride levels remained the same in the Mediterranean diet group, whereas it increased from 1.9 to 3.22 mmol L(-1) (P = 0.07) in the low-fat diet group. CONCLUSIONS: A Mediterranean diet seems to have an advantage over the low-fat diet in maintaining serum triglyceride levels and avoiding lipodystrophy, but this advantage was offset by a rise in cholesterol level. Several procedural and methodological issues were identified which must be rectified before a similar large-scale trial taking place.
