Gianluca Caridi1, Francesca Lugani1, Monica Dagnino1, Maddalena Gigante2, Achille Iolascon3, Mariateresa Falco3, Claudio Graziano4, Elisa Benetti5, Mauro Dugo6, Dorella Del Prete7, Antonio Granata8, Donella Borracelli9, Elisabetta Moggia10, Marco Quaglia11, Rita Rinaldi12, Loreto Gesualdo13, Gian Marco Ghiggeri1. 1. Laboratory on Pathophysiology of Uremia and Division of Nephrology, Dialysis, Transplantation, Istituto Giannina Gaslini, Genova, Italy. 2. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. 3. Department of Molecular Medicine and Medical Biotechnologies, University Federico II of Naples - CEINGE - Advanced Biotechnologies, Napoli, Italy. 4. Medical Genetics Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy. 5. Nephrology, Dialysis, Transplantation Unit, Azienda Ospedaliera-University of Padova, Padova, Italy. 6. Nefrologia, Dialisi, Trapianti Renali, O.C. Ca' Foncello, ULSS 9, Treviso, Italy. 7. Department of Medicine, Nephrology Unit, University of Padoa, Padova, Italy. 8. Nephrology and Dialysis Unit, 'San Giovanni di Dio' Hospital, Agrigento, Italy. 9. Nephrology and Dialysis Unit, Ospedale Alta Val D'Elsa, Poggibonsi, Siena, Italy. 10. Nephrology and Dialysis Unit, Ospedale S. Croce e Carle, Cuneo, Italy. 11. Nephrology and Transplantation Unit, Department of Translational Medicine, Azienda Ospedaliero-Universitaria 'Maggiore della Carità', 'Amedeo Avogadro' University, Novara, Italy. 12. Neurology Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy. 13. Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Abstract
BACKGROUND: Mutations of INF2 represent the major cause of familial autosomal dominant (AD) focal segmental glomerulosclerosis (FSGS). A few patients present neurological symptoms of Charcot-Marie-Tooth (CMT) disease but the prevalence of the association has not been assessed yet. METHODS: We screened 28 families with AD FSGS and identified 8 INF2 mutations in 9 families (32 patients overall), 3 of which were new. Mutations were in all cases localized in the diaphanous-inhibitory domain (DID) of the protein. RESULTS: Clinical features associated with INF2 mutations in our patient cohort included mild proteinuria (1.55 g/L; range 1-2.5) and haematuria as a unique symptom that was recognized at a median age of 21.75 years (range 8-30). Eighteen patients developed end-stage renal disease during their third decade of life; 12 patients presented a creatinine range between 1.2 and 1.5 mg/dL and 2 were healthy at 45 and 54 years of age. CMT was diagnosed in four cases (12.5%); one of these patients presented an already known mutation on exon 2 of INF2, whereas the other patients presented the same mutation on exon 4, a region that was not previously associated with CMT. CONCLUSIONS: We confirmed the high incidence of INF2 mutations in families with AD FSGS. The clinical phenotype was mild at the onset of the disease, but evolution to ESRD was frequent. The incidence of CMT has, for the first time, been calculated here to be 12.5% of mutation carriers. Our findings support INF2 gene analysis in families in which renal failure and/or neuro-sensorial defects are inherited following an AD model.
BACKGROUND: Mutations of INF2 represent the major cause of familial autosomal dominant (AD) focal segmental glomerulosclerosis (FSGS). A few patients present neurological symptoms of Charcot-Marie-Tooth (CMT) disease but the prevalence of the association has not been assessed yet. METHODS: We screened 28 families with AD FSGS and identified 8 INF2 mutations in 9 families (32 patients overall), 3 of which were new. Mutations were in all cases localized in the diaphanous-inhibitory domain (DID) of the protein. RESULTS: Clinical features associated with INF2 mutations in our patient cohort included mild proteinuria (1.55 g/L; range 1-2.5) and haematuria as a unique symptom that was recognized at a median age of 21.75 years (range 8-30). Eighteen patients developed end-stage renal disease during their third decade of life; 12 patients presented a creatinine range between 1.2 and 1.5 mg/dL and 2 were healthy at 45 and 54 years of age. CMT was diagnosed in four cases (12.5%); one of these patients presented an already known mutation on exon 2 of INF2, whereas the other patients presented the same mutation on exon 4, a region that was not previously associated with CMT. CONCLUSIONS: We confirmed the high incidence of INF2 mutations in families with AD FSGS. The clinical phenotype was mild at the onset of the disease, but evolution to ESRD was frequent. The incidence of CMT has, for the first time, been calculated here to be 12.5% of mutation carriers. Our findings support INF2 gene analysis in families in which renal failure and/or neuro-sensorial defects are inherited following an AD model.
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