The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite's digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT's native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.

BackgroundTetratricopeptide repeat domain 7A (TTC7A, chromosome 2p21) is a highly-conserved structural motif essential for multiprotein scaffolding and cell survival. Fewer than 60 cases of TTC7A deficiency have been reported globally. It produces multisystemic disease phenotypes which are lethal in two-thirds of patients, with a median survival age of 12 months. It is predominantly detected postnatally, often rendering medical and surgical interventions futile. Case presentationWe report the antenatal sonographic and magnetic resonance imaging characteristics of a novel phenotype of TTC7A-deficiency presenting with gastrointestinal atresia. This has never been previously documented. The diagnosis was confirmed via whole-exome next generation sequencing thus facilitating prompt initiation of management and prolonging viability. ConclusionsNovel insight into the prenatal morphological characteristics of TTC7A-deficiency phenotypes expands knowledge of this rare condition. Furthermore, antenatal recognition facilitates targeted investigation, genetic counselling, and earlier multidisciplinary intervention to prolong viability of this predominantly lethal condition.

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Background Tetratricopeptide repeat domain 7A (TTC7A, chromosome 2p21) is a highly conserved structural motif essential for multiprotein scaffolding and cell survival. Fewer than 60 cases of TTC7A deficiency have been reported globally. It produces multisystemic disease phenotypes which are lethal in two-thirds of patients, with a median survival age of 12 months. It is predominantly detected postnatally, often rendering medical and surgical interventions futile. Case presentation We report the antenatal sonographic and magnetic resonance imaging characteristics of a novel phenotype of TTC7A-deficiency presenting with gastrointestinal atresia. This has never been previously documented. The diagnosis was confirmed via whole-exome next-generation sequencing, thus facilitating prompt initiation of management and prolonging viability. Conclusions Novel insight into the prenatal morphological characteristics of TTC7A-deficiency phenotypes expands knowledge of this rare condition. Furthermore, antenatal recognition facilitates targeted investigation, genetic counselling, and earlier multidisciplinary intervention to prolong viability of this predominantly lethal condition.