ESPN 53rd Annual Meeting

ESPN 2021


 
Clinical delineation of the NUP93 glomerulopathy prevalent in Central and Eastern Europe.
JANKOWSKI MACIEJ 1 DACA-ROSZAK PATRYCJA 2 TRAUTMANN AGNES 3 MILOVANOVA ANASTASIIA 5 BALASZ-CHMIELEWSKA IRENA 4 GRENDA RYSZARD 6 ZIEG JAKUB 7 JANKAUSKIENE AUGUSTINA 8 SIMKOVA EVA 9 DROżDż DOROTA 11 SZYMANIK-GRZELAK HANNA 10 ŻUROWSKA ALEKSANDRA 4 TSYGIN ALEXEY 5 ZIęTKIEWICZ EWA 2 SCHAEFER FRANZ 3 LIPSKA-ZIęTKIEWICZ BEATA S. 12

1- DEPARTMENT OF BIOLOGY AND MEDICAL GENETICS, FACULTY OF MEDICINE, MEDICAL UNIVERSITY OF GDAńSK, GDAńSK, POLAND
2- INSTITUTE OF HUMAN GENETICS, POLISH ACADEMY OF SCIENCES, POZNAń, POLAND.
3- DIVISION OF PEDIATRIC NEPHROLOGY, CENTER FOR PEDIATRICS AND ADOLESCENT MEDICINE, UNIVERSITY OF HEIDELBERG, HEIDELBERG, GERMANY
4- DEPARTMENT OF PEDIATRICS, NEPHROLOGY AND HYPERTENSION, FACULTY OF MEDICINE, MEDICAL UNIVERSITY OF GDAńSK, GDAńSK, POLAND
5- DEPARTMENT OF NEPHROLOGY, NATIONAL MEDICAL AND RESEARCH CENTRE FOR CHILDREN’S HEALTH, MOSCOW, RUSSIA.
6- DEPARTMENT OF NEPHROLOGY, KIDNEY TRANSPLANTATION & HYPERTENSION, THE CHILDRENS MEMORIAL HEALTH INSTITUTE, WARSAW, POLAND
7- DEPARTMENT OF PAEDIATRICS, 2ND FACULTY OF MEDICINE, CHARLES UNIVERSITY IN PRAGUE AND UNIVERSITY HOSPITAL MOTOL, PRAGUE, CZECH REPUBLIC
8- CLINIC OF PEDIATRICS, INSTITUTE OF CLINICAL MEDICINE, FACULTY OF MEDICINE, VILNIUS UNIVERSITY, VILNIUS, LITHUANIA
9- DEPARTMENT OF PEDIATRIC NEPHROLOGY, DUBAI HOSPITAL, DUBAI, UNITED ARAB EMIRATES
10- DEPARTMENT OF PEDIATRICS AND NEPHROLOGY, MEDICAL UNIVERSITY OF WARSAW, WARSAW, POLAND
11- DEPARTMENT OF PEDIATRIC NEPHROLOGY AND HYPERTENSION, JAGIELLONIAN UNIVERSITY MEDICAL COLLEGE, CRACOW, POLAND
12- RARE DISEASES CENTRE AND CLINICAL GENETICS UNIT, DEPARTMENT OF BIOLOGY AND MEDICAL GENETICS, FACULTY OF MEDICINE, MEDICAL UNIVERSITY OF GDAńSK, GDAńSK, POLAND.
 
Introduction:

Molecular defects in genes encoding nucleoporins (NUPs; components of nuclear pore complexes), such as NUP93, have been recently reported to cause steroid-resistant nephrotic syndrome in childhood. Here we collected clinical and genetic information on 31 patients, including 20 unpublished, to further characterize the associated phenotype.

Material and methods:

The patients were recruited from the international PodoNet Registry clinical registry for patients with persistent subnephrotic proteinuria/overt steroid-resistant nephrotic syndrome and/or identified through systematic literature review. Clinical data were collected through a standardized questionnaire. The shared background haplotypes were determined and compared to general population; genetic clock methods were used to estimate the age of a mutation.

Results:

 Median age at onset was 4.4 (0.3-16) yrs. Most patients presented with overt nephrotic syndrome and 5 (16%) in end-stage kidney disease (ESKD), which was attained at a median age of 6 years. Extrarenal manifestations were present in a minority of cases and most commonly comprised cardiac disorders (19%) including severe dilated cardiomyopathy in 3 pts during peritoneal dialysis, eye abnormalities and vision difficulties (15%) and neurodevelopmental problems (7%).  

The c.1772G>T variant was found in 21 (including 10 homozygous) patients from Central and Eastern Europe (Poland, Czech, Germany, Hungary, Russia, Serbia) and Turkey. Patients homozygous for c.1772G>T had a milder disease course then other NUP93 cases with later median age at onset (5.0 vs 2.9, p=0.05) and at ESKD (11.0 vs 4.9 yrs; p=0.04). Analysis of the haplotype background composed of SNPs surrounding the variant revealed a common segment of at least 360 kb. Preliminary estimation of the non-recombined haplotypes suggests that the mutation occurred 600-1,500 years ago.

Conclusions:

The study enabled us to delineate the phenotype of NUP93 glomerulopathy, including a homogeneous group of SRNS patients of Central/Eastern European ethnicity who harbor a single founder mutation associated with a milder phenotype.