BLTP1 is required for survival and normal development and function of the neuromuscular junction in mice

BLTP1 (Bridge-Like Lipid Transfer Protein Family Member 1), previously known as Tweek, Kiaa1109, FSA or 4932438A13Rik, is a non-vesicular lipid transport protein linked to Alkuraya-Kučinskas Syndrome (AKS), an autosomal recessive disorder with severe brain malformations and arthrogryposis in humans. Although BLTP1 is known to be involved in the transfer of phospholipids between organellar membranes at membrane contact sites, its specific role during mammalian development remains poorly defined. Here we characterized the development of the neuromuscular junction (NMJ) in Bltp1 knockout ( Bltp1 –/– ) mice of either sex. These mutant mice die perinatally, exhibiting reduced growth of intramuscular motor nerves and a reduction in the size of the NMJ, compared to littermate controls. Electrophysiological analysis of the diaphragm muscle in Bltp1 –/– embryos reveals defects in synaptic transmission at the NMJ. Notably, the frequency of spontaneous neurotransmitter release is markedly increased, whereas evoked neurotransmitter release and quantal content are reduced. In addition, neuromuscular synapses in Bltp1 –/– mice fail to respond to a repetitive stimulation. Remarkably, the impairment of intramuscular nerve growth in Bltp1 –/– embryos is restored by supplementing pregnant dams with lecithin, a mixture of unsaturated phospholipids naturally present in foods, although lecithin supplement does not improve the overall survival of these mutant mice. Together, these results demonstrate that BLTP1 plays important roles during development for proper intramuscular nerve growth and neuromuscular synaptic function, and suggest that AKS patients may benefit from phospholipid supplementation such as lecithin. Significance Statement This paper characterizes the phenotype of mutant mice deficient in Bltp1 . We show that BLTP1 is required for survival and that BLTP1 plays important roles in normal development and function of the NMJ in mice.