Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1 , GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1 , FOXP1 , FOXG1 ), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population.

Genetic kidney diseases (GKDs) are a group of rare diseases, affecting approximately about 60 to 80 per 100,000 individuals, for which there is currently no treatment that can cure them (in many cases). GKDs usually leads to early-onset chronic kidney disease, which results in patients having to undergo dialysis or kidney transplant. Here, we briefly describe genetic causes and phenotypic effects of six GKDs representative of different ranges of prevalence and renal involvement (ciliopathy, glomerulopathy, and tubulopathy). One of the shared characteristics of GKDs is that most of them are monogenic. This characteristic makes it possible to use site-specific nuclease systems to edit the genes that cause GKDs and generate in vitro and in vivo models that reflect the genetic abnormalities of GKDs. We describe and compare these site-specific nuclease systems (zinc finger nucleases (ZFNs), transcription activator-like effect nucleases (TALENs) and regularly clustered short palindromic repeat-associated protein (CRISPR-Cas9)) and review how these systems have allowed the generation of cellular and animal GKDs models and how they have contributed to shed light on many still unknown fields in GKDs. We also indicate the main obstacles limiting the application of these systems in a more efficient way. The information provided here will be useful to gain an accurate understanding of the technological advances in the field of genome editing for GKDs, as well as to serve as a guide for the selection of both the genome editing tool and the gene delivery method most suitable for the successful development of GKDs models.

Hereditary renal tubulopathies are rare monogenic disorders caused by defects in tubular transport mechanisms that impair the handling of electrolytes, water, and acid–base balance along the nephron. While each tubulopathy is individually uncommon, their collective burden is clinically relevant, as these disorders can severely affect quality of life and predispose to nephrolithiasis, dehydration episodes, and progression to chronic kidney disease. Advances in molecular genetics have identified more than 70 genes involved in renal tubular physiology; however, a substantial proportion of these cases remain genetically unresolved, and marked phenotypic heterogeneity complicates diagnosis and management. This narrative review provides an integrated overview of the main transport systems operating in the different tubular segments of the nephron—proximal tubule, thick ascending limb of the loop of Henle, distal convoluted tubule and collecting duct—summarizing the tubulopathies associated with each segment and discussing in greater detail representative inherited disorders that illustrate the clinical consequences of their dysfunction. We highlight current diagnostic challenges and limitations of existing therapeutic strategies and discuss novel diagnostic approaches as well as emerging treatment options. Improved genetic diagnosis, validation of candidate biomarkers, and the development of novel therapeutic strategies will be essential to advance precision medicine and improve outcomes for patients with inherited renal tubulopathies.