Novel Fanconi renotubular syndromes provide insights in proximal tubule pathophysiology

• Published in: American journal of physiology. Renal physiology Vol. 320; no. 2; pp. F145 - F160
• Main Author: Lemaire, Mathieu
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2021
• Subjects: Fanconi Syndrome - diagnosis; Fanconi Syndrome - genetics; Fanconi Syndrome - physiopathology; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Kidney Tubules, Proximal - physiopathology; Mutation; rare genetic kidney disease; renal physiology; gene discovery; pathophysiology; Fanconi renotubular syndrome; proximal tubule; tubulopathy; genetic of kidney disease
• ISSN: 1931-857X; 1522-1466; 1522-1466
• DOI: 10.1152/ajprenal.00214.2020

The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase ( GATM), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 ( SLC34A1), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase ( EHHADH), hepatocyte nuclear factor 4A ( HNF4A), or NADH dehydrogenase complex I, assembly factor 6 ( NDUFAF6). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 ( SLC34A1). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.