Alessandra Pelle1,2, Alessandra Cuccurullo3,4, Cecilia Mancini5, Regina Sebastiano4, Giovanni Stallone6, Susanna Negrisolo7, Elisa Benetti7, Licia Peruzzi8, Michele Petrarulo9, Mario De Marchi3,4, Martino Marangella10, Antonio Amoroso5, Daniela Giachino3,4, Giorgia Mandrile3. 1. Department of Clinical and Biological Sciences, University of Torino, San Luigi University Hospital, Regione Gonzole 10, 10040, Orbassano, TO, Italy. alessandraelisapelle@gmail.com. 2. Medical Genetics Unit, San Luigi University Hospital, Orbassano, Italy. alessandraelisapelle@gmail.com. 3. Department of Clinical and Biological Sciences, University of Torino, San Luigi University Hospital, Regione Gonzole 10, 10040, Orbassano, TO, Italy. 4. Medical Genetics Unit, San Luigi University Hospital, Orbassano, Italy. 5. Department of Medical Sciences, Città della Salute e della Scienza, University of Torino, Turin, Italy. 6. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. 7. Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University of Padova, Padua, Italy. 8. Nephrology Dialysis Transplantation Unit, Città della Salute e della Scienza, Regina Margherita Children's Hospital, Turin, Italy. 9. S.C. Laboratorio Centrale, A. O. Ordine Mauriziano, Turin, Italy. 10. Fondazione Scientifica, A. O. Ordine Mauriziano, Turin, Italy.
Abstract
BACKGROUND: Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis. MATERIALS AND METHODS: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes. RESULTS: Two patients were heterozygous for two novel AGXT-promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells. CONCLUSION: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases.
BACKGROUND:Primary hyperoxaluria (PH) is a rare autosomal recessive disease commonly arising in childhood and presenting with nephrolithiasis, nephrocalcinosis and/or chronic renal failure. Three genes are currently known as responsible: alanine-glyoxylate aminotransferase (AGXT, PH type 1), glyoxylate reductase/hydroxypyruvate reductase (GRHPR, PH type 2), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1, PH type 3). In our Centre, at the end of 2014 molecular diagnosis of PH1 had been performed in 80 patients, while one patient received a PH2 diagnosis. MATERIALS AND METHODS: Fifteen patients referred to our Centre and suspected to have PH on clinical grounds were negative for pathogenic variants in the entire coding sequence and exon-intron boundaries of the AGXT gene. Therefore, we extended the analysis to the AGXT promoter region and the GRHPR and HOGA1 genes. RESULTS: Two patients were heterozygous for two novel AGXT-promoter variants (c.-647C > T, c.-424C > T) that were probably non pathogenic. One patient was homozygous for a novel HOGA1 variant of intron 2 (c.341-81delT), whose pathogenicity predicted by in silico splicing tools was not confirmed by a minigene splicing assay in COS-7 and HEK293T cells. CONCLUSION: New genetic subtypes of PH can be hypothesized in our patients, that may be caused by mutations in other gene encoding proteins of glyoxylate metabolism. Alternatively, some kind of mutations (e.g., deletions/duplications, deep intronic splicing regulatory variants) could be missed in a few cases, similarly to other genetic diseases.
Authors: Carla G Monico; Sandro Rossetti; Ruth Belostotsky; Andrea G Cogal; Regina M Herges; Barbara M Seide; Julie B Olson; Eric J Bergstrahl; Hugh J Williams; William E Haley; Yaacov Frishberg; Dawn S Milliner Journal: Clin J Am Soc Nephrol Date: 2011-09 Impact factor: 8.237
Authors: S Krishnamurthy; G B Kartha; V S Venkateswaran; M Prasannakumar; S Mahadevan; M Gowda; A Pelle; D Giachino Journal: Indian J Nephrol Date: 2017 Sep-Oct