Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus

Abstract

The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene 1 (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter 2 . Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans.NEUROD1 contains two exons and has been mapped to chromosome 2q (refs 5,6). We did not examine exon 1 because it is not translated 7 . Exon 2 encodes a protein with several distinct domains (Fig. 1a). We screened exon 2 and the flanking intron sequences for DNA sequence differences by direct sequencing of DNA samples from 94 individuals with type 2 diabetes. Each was the index case through which we ascertained 94 large families for the presence of diabetes segregating as an autosomal dominant disorder 8,9 .We examined exon 2 in all index cases and found four variants of the published sequence. The first was a single base-pair substitution, G→A, in codon 45 that results in an Ala→Thr substitution in the amino terminus of NEUROD1. The frequency of the threonine variant was similar in 94 index cases and in 96 unrelated non-diabetic individuals (32.9% and 35.9%, respectively). Similarly, this polymorphism was not associated with Fig. 1 Sequence differences found in NEUROD1. a, Schematic organization of NEUROD1 and its domains. Numbers refer to the amino acids bordering the domains. The details of the HLH domain are shown at the top. Filled arrows indicate mutations and the dotted arrows indicate the amino acid variants identified in NEUROD1.The borders were determined based on mammalian homology using published data 2 . 'tx/p300' indicates the transactivation domain as well as the p300-interacting region of NEUROD1 (refs 3,4). b, Alignment of the first 30 aa of the bHLH domain of NEUROD1 with other members of the basic HLH (bHLH) family. Residues responsible for DNA contact are underlined. The Arg 111 residue of NEUROD1 and the corresponding residues of MYOD and E47 are shown [16][17][18] (italics). c, A fragment of NEUROD1 sequence is shown, with the 2...

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