Kei Takasawa1, Atsumi Tsuji-Hosokawa1, Shigeru Takishima1,2, Yasunori Wada3, Keisuke Nagasaki4, Sumito Dateki5, Chikahiko Numakura6, Atsushi Hijikata7, Tsuyoshi Shirai7, Kenichi Kashimada1, Tomohiro Morio1. 1. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. 2. Department of Pediatrics, Soka Municipal Hospital, Soka, Japan. 3. Department of Pediatrics, Iwate Medical University School of Medicine, Morioka, Japan. 4. Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 5. Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 6. Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan. 7. Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
Abstract
BACKGROUND: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. RESULTS: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. CONCLUSIONS: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
BACKGROUND: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients. RESULTS: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment. CONCLUSIONS: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
Keywords:
A型胰岛素抵抗; Type A insulin resistance; insulin receptor (INSR) gene; lipodystrophy; small for gestational age (SGA); tyrosine kinase domain; 小于胎龄儿(SGA); 胰岛素受体(INSR)基因; 脂肪营养不良; 酪氨酸激酶结构域