MCKD2, FJHN and GCKD are associated with mutations of UMOD gene encoding the Tamm Horsfall glycoprotein. Most mutations are missense in the EGF-like domains and cause aggregates in tubular cells and reduced urinary secretion. Aim of the study was to investigate frequency of Uromodulinopathies among ESRF patients without etiologic diagnosis, registered in the kidney transplant regional waiting list of Piemonte. Inclusion criteria: alive, resident in Piemonte, <70 years, exclusion of known cause of renal loss, signed informed consent in agreement with Helsinki guidelines. Median age at ESRF was 47y, 61% male, 67% were transplanted in Piemonte (median age 51.8y). We analyzed UMOD hot spot region (exons 4 and 5, encoding the EGF-like domains) in 271 samples by DHPLC. Pathogenicity was evaluated by in silico analysis, cosegregation, absence in 100 controls. We identified 6 new missense mutations in 8 unrelated patients: A39T, C77S, C94Y, G105C, R212C were private and G88D recurred in 3 families with ancestry from the same area in the Veneto region. Four mutations affect Cysteines of the EGF-like domains. Median age at ESRF of UMOD patients was 57.6y (33.3-64.6) vs 46.9y (2.4-69.2) p=0.1. All were tranplanted at median age 59.8y. Their clinical presentation was often unremarkable. Seven patients had a positive family history of ESRF, so we directed patients and relatives to genetic counselling. This study contributes to the reassessment to a 3% frequency of Uromodulinopathies as a cause of ESRF of unknown origin in our population. The major finding is the important familiarity ascribed to other environmental factors (NSAID abuse). Disclosure of Financial Relationships: nothing to disclose
Uromodulinopathies May Show a Wider Phenotypic Spectrum and Be Responsible of as Many as 3% of Unspecific ESRF Cases
AMOROSO, Antonio;BENONI, SIMONA;GIACHINO, Daniela Francesca;MANDRILE, Giorgia;DE MARCHI, Mario
2008-01-01
Abstract
MCKD2, FJHN and GCKD are associated with mutations of UMOD gene encoding the Tamm Horsfall glycoprotein. Most mutations are missense in the EGF-like domains and cause aggregates in tubular cells and reduced urinary secretion. Aim of the study was to investigate frequency of Uromodulinopathies among ESRF patients without etiologic diagnosis, registered in the kidney transplant regional waiting list of Piemonte. Inclusion criteria: alive, resident in Piemonte, <70 years, exclusion of known cause of renal loss, signed informed consent in agreement with Helsinki guidelines. Median age at ESRF was 47y, 61% male, 67% were transplanted in Piemonte (median age 51.8y). We analyzed UMOD hot spot region (exons 4 and 5, encoding the EGF-like domains) in 271 samples by DHPLC. Pathogenicity was evaluated by in silico analysis, cosegregation, absence in 100 controls. We identified 6 new missense mutations in 8 unrelated patients: A39T, C77S, C94Y, G105C, R212C were private and G88D recurred in 3 families with ancestry from the same area in the Veneto region. Four mutations affect Cysteines of the EGF-like domains. Median age at ESRF of UMOD patients was 57.6y (33.3-64.6) vs 46.9y (2.4-69.2) p=0.1. All were tranplanted at median age 59.8y. Their clinical presentation was often unremarkable. Seven patients had a positive family history of ESRF, so we directed patients and relatives to genetic counselling. This study contributes to the reassessment to a 3% frequency of Uromodulinopathies as a cause of ESRF of unknown origin in our population. The major finding is the important familiarity ascribed to other environmental factors (NSAID abuse). Disclosure of Financial Relationships: nothing to disclose
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