PDX1-MODY: A rare missense mutation as a cause of monogenic diabetes |
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| Authors: | Gabriella de M. Abreu Roberta M. Tarantino Ana Carolina P. da Fonseca Ritiele B. de Souza Camila A.P.D. Soares Pedro H. Cabello Melanie Rodacki Lenita Zajdenverg Verônica M. Zembrzuski Mário Campos Junior |
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| Affiliation: | 5. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy;8. Children''s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;9. Department of Genetics, Children''s Hospital of Eastern Ontario, Ottawa, ON, Canada;1. Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada;2. Children''s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;3. Department of Genetics, Children''s Hospital of Eastern Ontario, Ottawa, ON, Canada;4. Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada;5. Department of Pathology and Laboratory Medicine, Children''s Hospital of Eastern Ontario, Ottawa, ON, Canada;6. Department of Pediatrics, Children''s Hospital of Eastern Ontario, Ottawa, ON, Canada;7. Newborn Screening Ontario, Children''s Hospital of Eastern Ontario, Ottawa, ON, Canada;1. Tuscany Regional Centre of Pediatric Diabetes, Meyer University Children''s Hospital, Florence, Italy;2. Medical Genetics Unit, Meyer University Children''s Hospital, Florence, Italy;3. University of Florence, Florence, Italy;4. Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences ‘Mario Serio’, University of Florence, Florence, Italy;1. Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland;2. University Hospital, Krakow, Poland;3. Center for Medical Genomics OMICRON, Poland;4. Department of Clinical Genetics and Laboratory Medical University, Lodz, Poland;5. Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland;1. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway;2. Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway;3. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway;4. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway;5. Department of Pathology, Haukeland University Hospital, Bergen, Norway;6. Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA;7. Department of Medicine, Brigham and Women''s Hospital, Harvard Medical School, Boston, MA, USA;1. Universidade do Estado da Bahia (UNEB), Salvador, Brazil;2. Disciplina de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil;3. Endocrinology Unit – Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil;4. Faculdade de Medicina da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil;5. Instituto da Criança, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;6. Monogenic Diabetes Group, Genetic Endocrinology Unit and Diabetes Unit, University of Sao Paulo (USP) Medical School, Sao Paulo, Brazil;7. Pediatric Endocrinology Unit, University Hospital Prof. Edgard Santos, Faculty of Medicine, Federal University of Bahia, Salvador, Brazil |
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| Abstract: | Maturity-Onset Diabetes of the Young type 4 is a rare form of diabetes mellitus, caused by mutations in the PDX1 gene. However, only a few mutations in this gene have been associated as a cause of monogenic diabetes up to date. It makes difficult to create a clinical manifestation profile of this disease and, consequently, to improve the therapeutic management for these patients. Here we report a normal weight woman, diagnosed with diabetes mellitus at 27 years old, during her first pregnancy. At the time of the recruitment, she was 40 years old and had a body mass index of 23.9 kg/m2, glycated hemoglobin level of 9.6%, and fasting plasma glucose (FPG) of 254 mg/dL. She presented no diabetic complications and she was being treated with insulin. She reported a family history of diabetes mellitus characteristic of an autosomal dominant mode of inheritance. Molecular analysis of the PDX1 gene revealed the missense variant c.532G > A (p.(Glu178Lys)) segregating from the patient to her son, reported as diabetic. It was absent in her healthy daughter. The c.532G > A seems to be a rare variant, absent in human variants databases, and among 86 normoglycemic controls. Eight in silico algorithms classified this variant as probably pathogenic. Additionally, analysis of the evolutionary conservation showed the glutamic acid in the position 178 of PDX-1 protein as conserved among several species. Our findings reinforce the importance of screening rare MODY genes among families with suspicion of monogenic diabetes to help better understand the clinical manifestations of this disease. |
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| Keywords: | Diabetes mellitus Monogenic diabetes MODY PDX1 MODY4 Mutation |
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