Lrig2 is required for maturation of peripheral nerves in the urinary bladder. Lrig2 is required for maturation of peripheral nerves in the urinary bladder

Leucine-rich-repeats and immunoglobulin-like-domains (LRIG2) variants can occur in urofacial syndrome (UFS), an inherited disease characterised by functional bladder outlet obstruction. We aimed to define the pathobiology underlying UFS which we hypothesised would illuminate how the bladder becomes innervated. Lrig2 was detected in pelvic ganglia supplying autonomic neurons to the bladder, and in neurites and glia emanating from explanted ganglia. One week old Lrig2 mutant mice displayed abnormally patterned bladder nerves, as did mice with mutations of Hpse2, also mutated in some UFS patients. From two weeks postnatally, Lrig2 mutants had urination defects resembling UFS. Molecules implicated in neural biology, including Nos1 which relaxes the bladder outlet, were dysregulated in newborn Lrig2 mutant bladders. These molecular aberrations preceded manifest urination defects. We discovered novel homozygous missense LRIG2 variants in non-syndromic bladder outlet obstruction. Molecules mutated in UFS are required for bladder innervation and LRIG2 variants can occur in non-syndromic bladder disease as well as in UFS.

富含亮氨酸重复序列和免疫球蛋白样结构域蛋白2（Leucine-rich-repeats and immunoglobulin-like-domains, LRIG2）变异可出现于面-泌尿综合征（urofacial syndrome, UFS）——一种以功能性膀胱出口梗阻为特征的遗传性疾病。本研究旨在明确UFS潜在的病理生物学机制，我们推测该机制可阐明膀胱的神经支配过程。研究人员在支配膀胱自主神经元的盆腔神经节，以及离体神经节衍生的神经突和神经胶质中检测到了Lrig2的表达。出生后1周的Lrig2突变小鼠表现出异常模式的膀胱神经，Hpse2突变小鼠也呈现相同异常——Hpse2在部分UFS患者中同样存在突变。自出生后2周起，Lrig2突变小鼠出现了与UFS相似的排尿功能障碍。涉及神经生物学的分子（包括可松弛膀胱出口的一氧化氮合酶1（Nos1））在新生Lrig2突变小鼠的膀胱中出现表达失调，此类分子异常早于显性排尿功能障碍出现。本研究在非综合征性膀胱出口梗阻患者中发现了新型纯合错义LRIG2变异。UFS中发生突变的分子对膀胱神经支配不可或缺，而LRIG2变异既可见于UFS，也可出现在非综合征性膀胱疾病中。