Neurogenic Defects Occur in LRIG2-Associated Urinary Bladder Disease.
Neurogenic Defects Occur in LRIG2-Associated Urinary Bladder Disease.
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LRIG2相关膀胱疾病中发生神经源缺陷。
DOI：
10.1016/j.ekir.2023.04.017
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发表时间：
2023-07
影响因子：
6
通讯作者：
Roberts, Neil A.
中科院分区：
文献类型：
--
作者：
Grenier, Celine;Lopes, Filipa M.;Cueto-Gonzalez, Anna M.;Rovira-Moreno, Eulalia;Gander, Romy;Jarvis, Benjamin W.;McCloskey, Karen D.;Gurney, Alison M.;Beaman, Glenda M.;Newman, William G.;Woolf, Adrian S.;Roberts, Neil A.
UFS是一种常染色体隐性遗传疾病，其特征是膀胱与逼尿肌平滑肌对抗未扩张的流出道收缩。它还具有异常的鬼脸。一半的UFS患者携带HPSE 2的双等位基因变异，而其他罕见的家族携带LRIG 2的变异。LRIG 2在盆腔神经节中被免疫检测到，将自主神经轴突送入膀胱。此外，Lrig 2突变小鼠具有异常排尿和异常模式的膀胱神经。我们假设周围神经源性缺陷是LRIG 2相关膀胱功能障碍的基础。我们描述了一个新的家庭与LRIG 2相关的UFS和研究Lrig 2纯合子突变小鼠离体生理分析。该索引病例产前出现尿路（UT）扩张，产后出现尿脓毒症和功能性膀胱出口梗阻。他的鬼脸，连同UT疾病，特点UFS。虽然HPSE 2测序正常，但他携带纯合的预测致病性LRIG 2终止突变（c.1939C>T; p.Arg647）。Lrig 2突变小鼠膀胱增大。离体生理学实验表明，神经源性平滑肌松弛缺陷的流出道，包含尿道毗邻膀胱，逼尿肌收缩。此外，两性之间在生理流出道缺陷方面存在细微差别。将该家族置于所有报告的UT疾病相关LRIG 2变体的背景下，全UFS表型发生双等位基因终止或移码变体，但错义变体导致膀胱局限性疾病。我们的鼠的观察结果支持这一假设，即UFS是一种遗传性自主神经病变的膀胱影响流出道和膀胱体功能。
Urofacial, or Ochoa, syndrome (UFS) is an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. It also features an abnormal grimace. Half of individuals with UFS carry biallelic variants in HPSE2, whereas other rare families carry variants in LRIG2.LRIG2 is immunodetected in pelvic ganglia sending autonomic axons into the bladder. Moreover, Lrig2 mutant mice have abnormal urination and abnormally patterned bladder nerves. We hypothesized that peripheral neurogenic defects underlie LRIG2-associated bladder dysfunction. We describe a new family with LRIG2-associated UFS and studied Lrig2 homozygous mutant mice with ex vivo physiological analyses. The index case presented antenatally with urinary tract (UT) dilatation, and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with UT disease, characterizes UFS. Although HPSE2 sequencing was normal, he carried a homozygous, predicted pathogenic, LRIG2 stop variant (c.1939C>T; p.Arg647∗). Lrig2 mutant mice had enlarged bladders. Ex vivo physiology experiments showed neurogenic smooth muscle relaxation defects in the outflow tract, containing the urethra adjoining the bladder, and in detrusor contractility. Moreover, there were nuanced differences in physiological outflow tract defects between the sexes. Putting this family in the context of all reported UT disease-associated LRIG2 variants, the full UFS phenotype occurs with biallelic stop or frameshift variants, but missense variants lead to bladder-limited disease. Our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.
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影响因子：
4.6
作者：
Hindi EA;Williams CJ;Zeef LAH;Lopes FM;Newman K;Davey MMM;Hodson NW;Hilton EN;Huang JL;Price KL;Roberts NA;Long DA;Woolf AS;Gardiner NJ
通讯作者：
Gardiner NJ
影响因子：
3.7
作者：
Hokke SN;Armitage JA;Puelles VG;Short KM;Jones L;Smyth IM;Bertram JF;Cullen-McEwen LA
通讯作者：
Cullen-McEwen LA
影响因子：
11.2
作者：
Duque, Sandra I.;Arnold, W. David;Odermatt, Philipp;Li, Xiaohui;Porensky, Paul N.;Schmelzer, Leah;Meyer, Kathrin;Kolb, Stephen J.;Schuemperli, Daniel;Kaspar, Brian K.;Burghes, Arthur H. M.
通讯作者：
Burghes, Arthur H. M.
影响因子：
3.7
作者：
通讯作者：
--
影响因子：
3.9
作者：
Jordan, Penelope;Dorval, Guillaume;Heidet, Laurence
通讯作者：
Heidet, Laurence