Our latest publications

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants
February 2024

In a recent collaborative effort, we describe the relevance of DNAJC3 as disease-causing gene in patients with hyperinsulinemic hypoglycaemia (HH). Our findings highlight the importance of clinicians screening for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism (CHI).

CHI is a rare genetic disorder that causes recurrent episodes of HH and is a component of various rare genetic syndromes (e.g. overgrowth syndromes, chromosomal and monogenic developmental syndromes, congenital disorders of glycosylation, syndromic channelopathies). The genetic and molecular mechanisms of CHI are diverse.

This report presents a case study of an individual with HH caused by DNAJC3 variants, a gene whose biallelic variants cause a multisystem disease, including early-onset diabetes mellitus. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Furthermore, the findings suggest that uncontrolled calcium flux from the ER to the cytosol is the most likely mechanism triggering insulin release in DNAJC3 deficiency. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis.

Our collaborative effort highlights the importance of close interactions between academia and the private sector as fruitful and complementary. The publication can be found here: https://www.mdpi.com/1422-0067/25/2/1270

The ciliary transition zone protein TMEM218 synergistically interacts with the NPHP module and its reduced dosage leads to a wide range of ciliopathies
March 2022

In a recent collaborative effort, we describe TMEM218 as a new disease gene for patients with a broad spectrum of syndromic ciliopathy phenotypes.

Mutations in genes that lead to dysfunctional cilia result in multisystemic disorders (ciliopathies) that can affect several organs such as the kidney, liver, heart, brain or the eye. Many ciliopathy-associated proteins localize to a distinct cellular compartment: the ciliary transition zone (TZ). We identified genetic variants in the gene encoding the transmembrane protein TMEM218 in patients with features related to Bardet-Biedl, Joubert and Meckel-Gruber syndrome. We characterize TMEM218 as a major component of the ciliary TZ module and provide evidence for an interaction of TMEM218 and the NPHP module crucial for proper ciliary function.

Our collaborative effort highlights the importance of close interactions between academia and the private sector as most fruitful and complementary. The publication can be found here:
https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddac027/6523245

 

Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice
July 2021

In patients with chronic kidney disease (CKD), the overall diagnostic yield of next generation sequencing (NGS) based-tests is ~30% for pediatric cases and ~6-30% for adult cases. Still, in reality, several barriers appear to hinder the implementation of NGS diagnostics in the routine clinical practice of nephrology.

To support nephrologists to overcome these barriers, we published an article in a great collaborative effort discussing the general items that are important to genetic testing in nephrology - namely (1) genetic testing modalities and their indications, (2) clinical information needed for high-quality interpretation of the genetic test, (3) clinical benefit of genetic testing and (4) genetic counselling.

A detailed description for the different groups of genetic kidney diseases and for CKD of unknown origin can be found here:
https://doi.org/10.1038/s41436-021-01127-8

 

The wind of change in the management of autosomal dominant polycystic kidney disease in childhood
March 2021

In recent years, significant progress has been made in understanding the genetic basis of ADPKD, quantifying disease manifestations in children and exploring very-early onset ADPKD as well as pharmacological delay of disease progression in adults. In collaboration with Djalila Mekahli and Charlotte Gimpel we propose an algorithm for work-up and management based on current recommendations that integrates the need to screen regularly for hypertension and proteinuria in offspring of affected parents. Furthermore, we discuss indications and scope of genetic testing in greater detail.

The full open-access article can be downloaded here: https://doi.org/10.1007/s00467-021-04974-4

 

 

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation
March 2021

A significant proportion of patients with chronic kidney disease are affected by monogenic kidney disorder. In a great collaboration with colleagues from the Charité and the Berlin Institute of Health (BIH) we screened the kidney transplantation waiting list at the Charité for patients with undetermined causes for chronic kidney disease (in total 635 patients) and investigated all genes described for renal and related diseases using Next-Generation Sequencing. Our study demonstrates the diagnostic value of comprehensive genetic testing in patients with unclear cause of chronic kidney disease.

The full open-access article can be downloaded here:
https://doi.org/10.1038/s41436-021-01127-8

Diagnosis and Management of Renal Cystic Disease of the Newborn
January 2021

Renal cystic diseases encompass various illnesses with different phenotypic expressions that can manifest in utero, throughout childhood, adolescence and adulthood. Cystic diseases may progress to potentially life-threatening chronic kidney disease, which is why the early detection and provision of effective management is essential. Together with colleagues from the US we examined the epidemiology, genetics, pathophysiology, diagnosis, presentation, and clinical management for renal cystic diseases, with particular attention to prenatal care and pregnancy counselling.

The full open-access article can be downloaded here:          
https://www.ajkd.org/article/S0272-6386(20)31194-X/fulltext

 

 

 

Collagen IVα345 dysfunction in glomerular basement membrane diseases. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases
January 2021

Diseases of the glomerular basement membrane (GBM), e.g. Goodpasture's disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure. Collagen IVα345 is an important architectural element of the GBM, but the how the collagen enables GBM to function as permselective filter and how defects cause renal failure is currently not known. We describe a distinctive genetic variant of collagen IVα345 associated with GP and AS and identify the sites on the collagen’s surface where pathogenic pathways of GP and AS (and potentially diabetic nephropathy) converge. We conclude that the structural assembly of the collagen is crucial for signaling and organizing macromolecular complexes that enable GBM assembly and function.

This collaborative effort is an important contribution, not only to the field of anti-GBM disease, but also for the understanding of GBM assembly, and for the connection between genetic disease and autoimmunity.

The full open-access article can be downloaded here: https://www.jbc.org/article/S0021-9258(21)00370-7/fulltext