Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder.
Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder.
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DOI：
10.3389/fgene.2022.896125
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发表时间：
2022
影响因子：
3.7
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中科院分区：
文献类型：
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尿面症（也称为奥乔亚）综合征（UFS）是一种常染色体隐性先天性膀胱疾病，以排尿功能障碍和微笑时的鬼脸为特征。编码分泌蛋白肝素酶-2的HPSE2的双等位基因变异在大约一半的基因研究家庭中被描述。Hpse2突变小鼠膀胱神经异常。我们试图扩大UFS的基因型谱，并深入了解其病理生物学。Sanger测序、下一代测序和微阵列分析在4个以前未报道的泌尿道疾病和鬼脸家族中进行。其中一个先证者患有肾衰竭，并且是先前描述的致病变异c.429T . >A, p.（Tyr143*）的纯合子。另外三个家庭各自携带了一种不同的新型HPSE2变体。其中一个外显子8和9有纯合三倍；另一个4号外显子纯合缺失；另一人携带了一种新的c.419C >0g变异，该变异与c.1099-1G> a（一种先前报道的致病性剪接变异）反式编码错义p.Pro140Arg。体外表达错义肝素酶-2变异表明其分泌正常，提示140Arg分泌后功能异常。膀胱自主神经元起源于盆腔神经节，其中常驻的神经细胞体来源于迁移的神经嵴细胞。我们证明，在正常的人类胚胎中，发育中的后肠和下尿路附近的神经元前体对肝素酶-2和富含亮氨酸的重复序列以及免疫球蛋白样结构域2 （LRIG2）均呈阳性。事实上，LRIG2的双等位变异与罕见的UFS家族有关。该研究扩大了UFS中HPSE2的基因型谱，并支持发育神经元病理生物学。
Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T>A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C>G variant encoding the missense p.Pro140Arg in trans with c.1099-1G>A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology.
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