ESPE Abstracts (2015) 84 FC10.6

Heterozygous Hypomorphic Mutation in the INS Gene could Cause Transient Neonatal Diabetes in Extremely Low Birth Weight Neonates

Tohru Yorifujia,b, Azumi Sakakibaraa, Yukiko Hashimotoa, Rie Kawakitaa,b, Yukiko Hosokawaa & Rika Fujimarua


aPediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan; bClinical Research Center, Osaka City General Hospital, Osaka, Japan


Background: Approximately 70% of transient neonatal diabetes mellitus (TNDM) are caused by abnormalities in the imprinted locus at chromosome 6q24, and the remaining 30% are caused by heterozygous mutations in the KATP-channel genes, ABCC8 or KCNJ11. Only a few cases of TNDM are reported to be caused by biallelic, recessive mutations in the insulin (INS) gene.

Objective and hypotheses: To explore the role of INS gene mutations as a cause of transient neonatal diabetes.

Method: (Subjects) Ten Japanese patients with transient neonatal diabetes who previously tested negative for abnormalities in the imprinted chromosome 6q24 locus and for mutations in the ABCC8 and KCNJ11 genes. (Methods) All three exons, exon-intron boundaries, and the 5′ upstream region of the INS gene were amplified from genomic DNA and directly sequenced. Additionally, the presence of the A23T substitution were tested by the mismatch primer PCR-RFLP analysis on 202 controls without diabetes and on 285 patients with late-onset diabetes.

Results: Out of the ten TNDM patients, we identified one patient with the heterozygous Q62* mutation and five patients with the A23T substitution in the signal peptide. On the contrary, the A23T was found in only 7/202 normal controls and in 25/285 of late-onset diabetes patients. Interestingly, fout patients with the INS gene alterations were born with an extremely low birth weight (ELBW, <1000 g) and the hyperglycaemia resolved spontaneously by 2 months of age.

Conclusion: Heterozygous hypomorphic mutation in the INS gene could cause TNDM in ELBW neonates. The A23T substitution previously believed to be a rare polymorphism without functional significance was strongly associated with TNDM of ELBW neonates in Japanese.

Funding: This work was suppoted in part by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan to TY (No. 15K09636).

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