Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations.
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans.
Department of Human Genetics.
Anne
A
Kosfeld
Department of Human Genetics.
Frank
F
Brand
Institute of Molecular Biology.
Anna-Carina
AC
Weiss
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Martin
M
Kreuzer
Department of Nephropathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Michaela
M
Goerk
Department of Human Genetics.
Helge
H
Martens
Department of Human Genetics.
Stephanie
S
Schubert
Institute of Molecular Biology.
Anne-Kathrin
AK
Schäfer
Department of Human Genetics.
Vera
V
Riehmer
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Imke
I
Hennies
Department of Pathology, Hannover Medical School, Hannover, Germany.
Jan Hinrich
JH
Bräsen
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Lars
L
Pape
Department of Nephropathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Kerstin
K
Amann
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Lars
L
Krogvold
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Anna
A
Bjerre
Department of Nephropathology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Christoph
C
Daniel
Institute of Molecular Biology.
Andreas
A
Kispert
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Dieter
D
Haffner
Department of Human Genetics.
Ruthild G
RG
Weber
D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007668:Kidney / Q000002:abnormalities / Q000473:pathology; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D053606:Receptors, OSM-LIF / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014513:Ureter / Q000002:abnormalities / Q000473:pathology; D014551:Urinary Tract / Q000473:pathology; D014564:Urogenital Abnormalities / Q000235:genetics*
C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D053606:Receptors, OSM-LIF