Molecular mechanisms of insulin resistance in 2 cases of primary insulin receptor defect-associated diseases.
BACKGROUND
Defects of the insulin receptor gene ( INSR ) cause wide spectra of congenital insulin resistance. Monoallelic defects result in milder insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN, type A). Whereas, leprechaunism (Donahue syndrome), the most severe condition with lethality during the infantile period is caused by biallelic defects of INSR .


METHODS
We detected 2 missense mutations in 2 cases of leprechaunism and IRAN, type A, and reduced mRNA expression in the leprechaunism case. We performed an in vitro analysis to confirm that the 2 missense mutations are causative.


RESULTS
The heterozygote mutations c.3436G>A (p.Gly1146Arg) and c.294C>A (p.Ser98Arg) were identified in a male patient with IRAN, type A and a female patient with leprechaunism, respectively. Gly1146Arg was previously reported in a diabetic case without precise functional analyses, and Ser98Arg is a novel mutation. Gly1146 and Ser98 are located on the tyrosine kinase domain and ligand-binding domain of INSR, respectively, and in vitro analyses (assay for insulin binding and phosphorylation) revealed that each mutation disrupted protein functions and properties. In the leprechaunism case, mutations in INSR other than Ser98Arg were not identified, and qRT-PCR analysis revealed that mRNA expression of INSR in lymphocytes was reduced in the leprechaunism case.


CONCLUSIONS
Our study indicates that the 2 missense mutations of INSR , Gly1146Arg, and Ser98Arg, are responsible for insulin resistance, and, suggests that mutations not contained within INSR , but leading to decreased INSR expression should be considered for the patients who show insulin resistance without any mutations in the coding sequence of INSR.
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Atsumi
A
Tsuji-Hosokawa
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Kei
http://orcid.org/0000-0001-6947-4034
K
Takasawa
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Risa
R
Nomura
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Yuichi
Y
Miyakawa
Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
Chikahiko
C
Numakura
Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
Atsushi
A
Hijikata
Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
Tsuyoshi
T
Shirai
Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
Yoshihiro
Y
Ogawa
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Kenichi
K
Kashimada
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
Tomohiro
T
Morio
D000052:Acanthosis Nigricans / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002648:Child; D003920:Diabetes Mellitus / Q000235:genetics*; D056731:Donohue Syndrome / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D055550:Protein Stability; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism
D015703:Antigens, CD; C435941:INSR protein, human; D011972:Receptor, Insulin
congenital insulin resistance; insulin receptor; insulin-resistant diabetes mellitus with acanthusis nigricans; leprechaunism