Mutational Spectrum of CYP24A1 Gene in a Cohort of Italian Patients with Idiopathic Infantile Hypercalcemia
| Autor: | Gianluca Caridi, Gian Marco Ghiggeri, Maddalena Gigante, Emma Diletta Stea, Maria Michela D'Alessandro, Vincenza Carbone, Mario Giordano, Giuseppe Grandaliano, Loreto Gesualdo, Luisa Santangelo, Sterpeta Diella, Lucia Argentiero, Silvio Maringhini, Gianluigi Ardissino, Marida Martino, Domenico Scrutinio, Silvana Pepe |
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| Rok vydání: | 2016 |
| Předmět: |
Vitamin
Mutation business.industry 030232 urology & nephrology Vitamin D3 24-Hydroxylase medicine.disease medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry CYP24A1 Cohort Immunology medicine Cancer research 030212 general & internal medicine Nephrocalcinosis business Gene Cohort study |
| Zdroj: | Nephron. 133:193-204 |
| ISSN: | 2235-3186 1660-8151 |
| Popis: | Background/Aims: Loss-of-function mutations in the CYP24A1 gene, which encodes the vitamin D-24 hydroxylase, have been recognized as a cause of elevated 1,25-dihydroxyvitamin D concentrations, hypercalcemia, hypercalciuria, nephrocalcinosis and nephrolithiasis in infants and adults. As only a case report describing 2 adult patients has been reported in Italian population, we report here the mutation analysis of CYP24A1 gene in an Italian cohort of 12 pediatric and adult patients with idiopathic infantile hypercalcemia (IIH). Methods: We performed mutational screening of CYP24A1 gene in a cohort of 12 Italian patients: 8 children with nephrocalcinosis, hypercalcemia and PTH levels CYP24A1 gene was analysed in all patients and family members by polymerase chain reaction and direct sequencing. The potential pathogenicity of the newly identified missense mutations was evaluated by 3 different in silico approaches (Sorting Intolerant from Tolerant, Polyphen and Mutation Taster) and by comparative analysis in 14 different species using ClustalW software. Results:CYP24A1 bi-allelic mutations were found in 8 individuals from 7 Italian families (7/11; 64%). Overall, 6 different CYP24A1 mutations, including one small deletion (p.Glu143del), 4 missense mutations (p.Leu148Pro; p.Arg396Trp; p.Pro503Leu; p.Glu383Gln) and one nonsense mutation (p.Tyr220*) were identified. Two out of 6 mutations (p.Tyr220* and p.Pro503Leu) were not previously described. Moreover, a new CYP24A1 variant was identified by genetic screening of asymptomatic controls. Conclusion: To the best of our knowledge, this is the first report of a CYP24A1 molecular analysis performed in an Italian cohort of adult and pediatric Italian patients. This study (1) confirms that CYP24A1 plays a causal role in some but not all cases of IIH (64%); (2) expands the spectrum of known CYP24A1 pathogenic mutations; (3) describes 2 hotspots detected in 50% of all Italian cases; and (4) emphasizes the importance of recognition and genetic diagnosis of CYP24A1 defects in infantile as well as adult hypercalcemia. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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