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 nonvesicular 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 <i>Bltp1</i> knock-out (<i>Bltp1^-/-</i> ) 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 with littermate controls. Electrophysiological analysis of the diaphragm muscle in <i>Bltp1</i> ^-/- 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 <i>Bltp1</i> ^-/- mice fail to respond to a repetitive stimulation. Remarkably, the impairment of intramuscular nerve growth in <i>Bltp1^-/-</i> 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.