High-throughput mutation analysis for known and novel single-gene causes of kidney stones and related disorders

对肾结石及相关疾病的已知和新的单基因原因进行高通量突变分析

• 批准号: 291110008
• 负责人: Professor Dr. Jan Halbritter
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Nephrologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/291110008?language=en
• 关键词: throughput; mutation; analysis; known; novel

Kidney stone disease comprises nephrolithiasis (NL) and nephrocalcinosis (NC). NL and NC are highly prevalent conditions in the general population (~10%) associated with significant morbidity and progression to chronic kidney disease (CKD). Its etiology is multifactorial with an environmental and a genetic component. Although the heritability has been estimated to 56% and more than 30 monogenic causes have been identified, the genetic basis of NL/NC remains largely unknown. Furthermore, for most patients with NL/NC, mutation analysis in causative genes has not been accessible so far, despite the fact that knowledge of the molecular cause of NL/NC may have important consequences for prognosis, prophylaxis and/or treatment. We hypothesize that the fraction of monogenic causes to the overall population of kidney stone formers is significantly higher than generally assumed. We recently developed a novel high-throughput mutation analysis approach that allows to simultaneously examine multiple genes in multiple individuals at very low cost. In a pilot-study we demonstrated the power of the technique in 268 unrelated patients with NL/NC. We thereby identified the molecular cause in 15% (40/268), further suggesting that the role of single-gene causes in NL/NC is indeed underestimated. With this proposal we aim to investigate two main goals: 1) Determination of the prevalence of >30 known monogenic causes in a clinically well-defined cohort of ~600 individuals with NL/NC, as well as characterizing genotype-phenotype correlations, related to age-of-onset and manifestation of CKD. 2) Identification of novel disease genes by whole exome/genome sequencing AND candidate gene analysis in subjects without prior findings in known genes. Implementation of this proposal will broaden the knowledge of the molecular basis of NL/NC. By identification of new disease mechanisms, this project may contribute to develop novel therapeutic targets and help to establish a more personalized treatment.

肾结石病包括肾结石（NL）和肾钙质沉着（NC）。NL和NC是一般人群中的高患病率疾病（约10%），与显著的发病率和慢性肾脏疾病（CKD）进展相关。其病因是多因素的，有环境因素和遗传因素。虽然遗传率估计为56%，并已确定了30多个单基因的原因，NL/NC的遗传基础在很大程度上仍然未知。此外，对于大多数NL/NC患者，致病基因的突变分析迄今尚未获得，尽管NL/NC的分子原因的知识可能对预后，预防和/或治疗有重要影响。我们假设单基因原因在肾结石患者中所占比例明显高于一般假设。我们最近开发了一种新的高通量突变分析方法，允许以非常低的成本同时检查多个个体中的多个基因。在一项初步研究中，我们证明了该技术在268例无关的NL/NC患者中的功效。因此，我们在15%（40/268）中确定了分子原因，进一步表明NL/NC中单基因原因的作用确实被低估了。通过该提议，我们旨在研究两个主要目标：1）在约600名NL/NC个体的临床明确定义的队列中确定>30种已知单基因原因的患病率，以及表征与发病年龄和CKD表现相关的基因型-表型相关性。2)通过全外显子组/基因组测序和候选基因分析，在先前未发现已知基因的受试者中鉴定新的疾病基因。该提案的实施将拓宽NL/NC分子基础的知识。通过识别新的疾病机制，该项目可能有助于开发新的治疗靶点并帮助建立更个性化的治疗方法。

项目成果

Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis

• DOI: 10.1007/s00439-019-01978-x
• 发表时间: 2019-03-01
• 期刊: HUMAN GENETICS
• 影响因子: 5.3
• 作者: Amar, Ali;Majmundar, Amar J.;Hildebrandt, Friedhelm
• 通讯作者: Hildebrandt, Friedhelm

Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment.

• DOI: 10.1016/j.kint.2020.05.027
• 发表时间: 2020-10
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Schönauer R;Jin W;Ertel A;Nemitz-Kliemchen M;Panitz N;Hantmann E;Seidel A;Braun DA;Shril S;Hansen M;Shahzad K;Sandford R;Saunier S;Benmerah A;Bergmann C;Hildebrandt F;Halbritter J
• 通讯作者: Halbritter J

Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between WT1 and PKD1

• DOI: 10.1136/jmedgenet-2019-106633
• 发表时间: 2020-05
• 期刊: Journal of Medical Genetics
• 影响因子: 4
• 作者: Johannes Münch;K. Kirschner;H. Schlee;C. Kraus;Ria Schönauer;W. Jin;D. Le Duc;H. Scholz;J. Halbritter

Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes

• DOI: 10.1038/s41436-020-0816-3
• 发表时间: 2020-05-13
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Schoenauer, Ria;Baatz, Sebastian;Halbritter, Jan
• 通讯作者: Halbritter, Jan

Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting

• DOI: 10.1007/s00240-019-01116-2
• 发表时间: 2019-12-01
• 期刊: UROLITHIASIS
• 影响因子: 3.1
• 作者: Schoenauer, Ria;Petzold, Friederike;Halbritter, Jan
• 通讯作者: Halbritter, Jan