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Introduction
Maturity-onset diabetes of the young (MODY) is a subtype of diabetes mellitus (DM) caused by a single gene disorder, mostly related to pancreatic β-cell development and function. The clinical characteristics of MODY include early onset of DM, typically before the age of 25 years, and no history of obesity or presence of autoantibodies against β cells despite the younger age of onset1. Advances in genomic research have enabled the identification of gene variants responsible for Mendelian diseases2. Pancreatic and duodenal homeobox 1 (PDX1) gene is the fourth causative gene of MODY, PDX1-MODY (MODY4). PDX1 is a transactivator essential for pancreatic development and insulin secretion and is expressed mainly in the duodenum, gall bladder, pancreas, small intestine and stomach3. Information on the clinical characteristics and pathogenesis of the variants in patients with PDX1-MODY, however, is limited. Here, we report a large MODY family associated with a novel PDX1 variant and a second family with the pathogenic variant previously reported but not analyzed on the basis of in vitro functional analysis.
Case presentation
Two Japanese probands were referred to our hospital for glycemic management. The pedigrees and clinical characteristics are presented in Fig. 1a and Table 1.
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Fig. 1
Pedigrees and variants information.
A The pedigree of the probands. In family 1, the parents of the proband were diagnosed with DM—the father (II-3) at 45 years od age and the mother (II-4) at 59 years of age. The proband’s older sister (III-2) was diagnosed at 13 years of age and died at 32 years of age due to end-stage renal disease. His daughter (IV-5) developed DM at 16 years of age in 2010. Five family members, including the proband, were diagnosed with DM before 25 years of age. The grandfather (I-3) of proband 2 was diagnosed with DM in his 40 s and placed on insulin therapy. He had blindness due to diabetic retinopathy. B Sanger sequencing chromatograms. Top: the wild-type sequence as the control. Bottom: the variants (indicated by arrows) found in each proband. C The aspartic acid residue at this position is highly conserved across species. D A HiBiT luminescence assay showing intracellular PDX1 expression in HEK293T cells. Luminescence was significantly reduced in cells expressing PDX1:c.C442G p.(Arg148Gly) compared with...