Majdi Nagara1, Gregory Papagregoriou2, Rim Ben Abdallah3, Zied Landoulsi4, Yosra Bouyacoub4, Sahar Elouej4, Rym Kefi4, Tommaso Pippucci5, Konstantinos Voskarides2, Anu Bashamboo6, Kenneth McElreavey6, Mongia Hachicha3, Giovanni Romeo5, Marco Seri5, Constantinos Deltas2, Sonia Abdelhak4. 1. Institut Pasteur de Tunis, Laboratoire de Génomique Biomédicale et Oncogénétique (LR11IPT05), 1002 Tunis, Tunisia; Aix Marseille University, Medical Genetics & Functional Genomics, UMR_S 910 Inserm, 13385 Marseille, France. Electronic address: majdi.nagara@univ-amu.fr. 2. Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus. 3. Pediatric Department, Hédi Chaker Hospital, Sfax, Tunisia. 4. Institut Pasteur de Tunis, Laboratoire de Génomique Biomédicale et Oncogénétique (LR11IPT05), 1002 Tunis, Tunisia. 5. U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy. 6. Human Developmental Genetics, Institut Pasteur, Paris, France.
Abstract
AIM OF THE STUDY: Recent advances in understanding the underlying molecular mechanism for distal renal tubular acidosis (dRTA), led to an increased attention towards the primary and the familial forms of the disease. Mutations in ATP6V1B1 and ATP6V0A4 are usually responsible for the recessive form of the disease. Mutations in gene AE1 encoding the Cl-/HCO3- exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Our objective is to identify the mutational spectrum responsible of dRTA in a consanguineous Libyan family. MATERIALS AND METHODS: Both ATP6V0A4 and ATP6V1B1 genes were preferentially screened in our patient. Additional whole exome sequencing (WES) in the same patient, offered a wider view on potential chromosomal rearrangements as well as the mutational spectrum of other genes involved in this disease. RESULTS: The patient is a heterozygote for two different mutations, one in each of the genes ATP6V0A4 and ATP6V1B1, while no deleterious variation was detected in the remaining genes responsible for the recessive form of dRTA. Homozygosity mapping and WES confirmed our findings and supported the hypothesis of a digenic inheritance model existing as an explanation for dRTA. CONCLUSIONS: To our knowledge, this is the first report describing a Libyan patient with dRTA who suffered from early-onset sensorineural hearing loss, with a digenic mode of inheritance, supported by the identification of two novel mutations. This study increases the understanding of how dRTA is genetically transmitted, while offers a good outline towards the molecular diagnostics and genetic counseling for dRTA in Lybians.
AIM OF THE STUDY: Recent advances in understanding the underlying molecular mechanism for distal renal tubular acidosis (dRTA), led to an increased attention towards the primary and the familial forms of the disease. Mutations in ATP6V1B1 and ATP6V0A4 are usually responsible for the recessive form of the disease. Mutations in gene AE1 encoding the Cl-/HCO3- exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Our objective is to identify the mutational spectrum responsible of dRTA in a consanguineous Libyan family. MATERIALS AND METHODS: Both ATP6V0A4 and ATP6V1B1 genes were preferentially screened in our patient. Additional whole exome sequencing (WES) in the same patient, offered a wider view on potential chromosomal rearrangements as well as the mutational spectrum of other genes involved in this disease. RESULTS: The patient is a heterozygote for two different mutations, one in each of the genes ATP6V0A4 and ATP6V1B1, while no deleterious variation was detected in the remaining genes responsible for the recessive form of dRTA. Homozygosity mapping and WES confirmed our findings and supported the hypothesis of a digenic inheritance model existing as an explanation for dRTA. CONCLUSIONS: To our knowledge, this is the first report describing a Libyan patient with dRTA who suffered from early-onset sensorineural hearing loss, with a digenic mode of inheritance, supported by the identification of two novel mutations. This study increases the understanding of how dRTA is genetically transmitted, while offers a good outline towards the molecular diagnostics and genetic counseling for dRTA in Lybians.
Authors: Denisa Hathazi; Helen Griffin; Matthew J Jennings; Michele Giunta; Juliane S Müller; Christopher Powell; Sarah F Pearce; Benjamin Munro; Wei Wei; Veronika Boczonadi; Joanna Poulton; Angela Pyle; Claudia Calabrese; Aurora Gomez-Duran; Ulrike Schara; Robert D S Pitceathly; Michael G Hanna; Kairit Joost; Ana Cotta; Julia Filardi Paim; Monica Machado Navarro; Jennifer Duff; Andre Mattman; Kristine Chapman; Serenella Servidei; Adela Della Marina; Johanna Uusimaa; Andreas Roos; Vamsi Mootha; Michio Hirano; Mar Tulinius; Mamta Giri; Eric P Hoffmann; Hanns Lochmüller; Salvatore DiMauro; Michal Minczuk; Patrick F Chinnery; Rita Horvath Journal: EMBO J Date: 2020-10-31 Impact factor: 14.012