Identification of a novel UMOD mutation (c.163G>A) in a Brazilian family with autosomal dominant tubulointerstitial kidney disease

Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.

Figure 1.. Family pedigree. The arrow indicates the index case. The double arrow indicates the patient who donated a kidney and still had an estimated glomerular filtration rate (eGFR) of 66 mL·min^-1/(1.73m²) at age 59. One transverse bar means death by unknown cause whereas two transverse bars mean death in hemodialysis. Black figures indicate end stage renal disease or eGFR <60 mL·min^-1/(1.73m²). Gray figures indicate eGFR >60 and <90 mL·min^-1/(1.73m²). For patients affected clinically, see Supplementary Table S1 for details. A plus sign (+) indicates that the patient was genetically tested and found to have the UMOD mutation. A negative sign (−) means the patient was genetically tested and found not to have a UMOD mutation.

Figure 2.. Renal biopsy photomicrography and ultrasound images. A, Normal glomerulus (hematoxylin-eosin; bar=50 µm). B, Tubulointerstitial area; mild interstitial fibrosis and tubular atrophy with mononuclear and eosinophilic inflammatory infiltrate (hematoxylin-eosin, bar=50 µm). C, Negative immunostaining of the glomerulus for immunoglobulin G. (A, B and C from case IV:6). D, Renal ultrasound image showing hyperechogenic kidney with cortical cyst from case III:9.

Figure 3.. Sequence analysis, evolutionary conservation and uromodulin protein diagram. A, UMOD gene analysis at exon 4 from the index case and two family members from other generations. The sequence analysis showed a novel heterozygous missense mutation, G163A, resulting in a G55S amino acid exchange. The arrow indicates the overlapping peaks at the site of nucleotide substitution. All positive patients presented the same mutation. The cases are III:9, IV:6 and V:2, respectively. B, Conservation of the mutated amino acid G55 residue (boxed) among mammals. C, Structure of the uromodulin protein, showing a leader peptide, three epidermal growth factor EGF-like domains, a central domain named D8C, a ZP domain and a glycosylphosphatidylinositol GPI-anchoring site; the black arrow shows the heterozygous missense mutation c.G163A; p.Gly55Ser, found in the present study, located in EGF1 domain. Below each region are the percentages of mutations reported to date.