PDF(Pubmed)
Abstract：
UNASSIGNED: Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain a proportion of cases. Aim of this study was to unravel the underlying molecular mechanism of syndromic CAKUT in two multiplex families with presumed autosomal recessive inheritance.
UNASSIGNED: ES in the index individuals revealed two different rare homozygous variants in FOXD2, a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans with FOXD2 dysfunction. To study the pathomechanism of FOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology of Foxd2 KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests that FOXD2 could play a role for maintenance of podocyte integrity during adulthood.
UNASSIGNED: In summary, our data implicate that FOXD2 dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.
UNASSIGNED: ES in the index individuals revealed two different rare homozygous variants in FOXD2, a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans with FOXD2 dysfunction. To study the pathomechanism of FOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology of Foxd2 KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests that FOXD2 could play a role for maintenance of podocyte integrity during adulthood.
UNASSIGNED: In summary, our data implicate that FOXD2 dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.
摘要：
■先天性肾脏和泌尿道异常（CAKUT）是30岁以下慢性肾脏疾病的主要原因。许多单基因形式的发现主要是由于全面的基因检测，如外显子组测序（ES）。然而,已知疾病相关基因中的致病变异仍然只能解释部分病例。这项研究的目的是揭示两个假定常染色体隐性遗传的多重家族中综合征性CAKUT的潜在分子机制。
■索引个体中的ES揭示了FOXD2中两种不同的罕见纯合变体，FOXD2是一种以前与人类CAKUT无关的转录因子：家族1中的移码和家族2中的错义变体，具有与常染色体隐性遗传一致的家族分离模式。CRISPR/Cas9衍生的Foxd2敲除（KO）小鼠表现为双侧肾盂扩张伴有肾乳头萎缩，而肾外特征包括下颌，眼科,和行为异常，概述患有FOXD2功能障碍的人类的表型。研究FOXD2-功能障碍介导的发育性肾脏缺陷的病理机制，以互补的方式，我们在输尿管芽诱导的小鼠后肾间质细胞中产生了CRISPR/Cas9介导的Foxd2KO。转录组学分析揭示了许多在肾脏/泌尿生殖发育中重要的差异表达基因的富集。包括Pax2和Wnt4以及表明细胞身份向基质细胞身份转变的基因表达变化。Foxd2KO小鼠肾脏的组织学证实纤维化增加。Further,GWAS数据（全基因组关联研究）表明，FOXD2可以在成年期间维持足细胞的完整性。
■总之，我们的数据提示FOXD2功能障碍是常染色体隐性遗传综合征CAKUT的一个非常罕见的原因,并提示PAX2-WNT4细胞信号轴的紊乱促成了这种表型.
■索引个体中的ES揭示了FOXD2中两种不同的罕见纯合变体，FOXD2是一种以前与人类CAKUT无关的转录因子：家族1中的移码和家族2中的错义变体，具有与常染色体隐性遗传一致的家族分离模式。CRISPR/Cas9衍生的Foxd2敲除（KO）小鼠表现为双侧肾盂扩张伴有肾乳头萎缩，而肾外特征包括下颌，眼科,和行为异常，概述患有FOXD2功能障碍的人类的表型。研究FOXD2-功能障碍介导的发育性肾脏缺陷的病理机制，以互补的方式，我们在输尿管芽诱导的小鼠后肾间质细胞中产生了CRISPR/Cas9介导的Foxd2KO。转录组学分析揭示了许多在肾脏/泌尿生殖发育中重要的差异表达基因的富集。包括Pax2和Wnt4以及表明细胞身份向基质细胞身份转变的基因表达变化。Foxd2KO小鼠肾脏的组织学证实纤维化增加。Further,GWAS数据（全基因组关联研究）表明，FOXD2可以在成年期间维持足细胞的完整性。
■总之，我们的数据提示FOXD2功能障碍是常染色体隐性遗传综合征CAKUT的一个非常罕见的原因,并提示PAX2-WNT4细胞信号轴的紊乱促成了这种表型.
