Abstract
The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.
Highlights
Cystic diseases of the kidney are comprised of a diverse group of acquired, hereditary, and developmental disorders where renal cysts are the common denominator driving kidney failure
Cystic kidney diseases that are genetic in origin, i.e., are caused by germ-line mutations occurring in single genes, are inherited as Mendelian traits in an autosomal dominant or recessive manner [2]
While traditional positional cloning strategies laid the groundwork, next-generation sequencing (NGS) substantially accelerated our pace of identifying the pathogenic genes responsible for cystic kidney diseases, with over 50 new NPHP genes alone identified in the last 10 years [3]. Given this surge of findings, and that they are the most frequent genetic cause of end-stage renal disease (ESRD) in the first three decades of life, this review focuses on subjects central to understanding the pathobiology of NPHP and NPHP related ciliopathies (NPHP-RC)
Summary
Cystic diseases of the kidney are comprised of a diverse group of acquired, hereditary, and developmental disorders where renal cysts are the common denominator driving kidney failure. Cystic kidney diseases that are genetic in origin, i.e., are caused by germ-line mutations occurring in single genes ( termed monogenic), are inherited as Mendelian traits in an autosomal dominant or recessive manner [2] Proteins encoded by these cystogenic genes are almost always localised in the primary cilium of the cell and, these cystic kidney diseases are termed ciliopathies (disease of the cilia). While traditional positional cloning strategies laid the groundwork, next-generation sequencing (NGS) substantially accelerated our pace of identifying the pathogenic genes responsible for cystic kidney diseases, with over 50 new NPHP genes alone identified in the last 10 years [3] Given this surge of findings, and that they are the most frequent genetic cause of end-stage renal disease (ESRD) in the first three decades of life, this review focuses on subjects central to understanding the pathobiology of NPHP and NPHP-RC. We review current progress made in the understanding of the molecular mechanisms causing NPHP and diagnosis, management strategies, and unmet clinical and research needs are discussed
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