Lisa I. S. Allen

Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with early-onset diabetes and nondiabetic renal disease-particularly renal cystic disease. We investigated a possible role for the HNF-1beta gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1beta gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1beta mutations.

Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

The transcription factor insulin promoter factor-1 (IPF-1) plays a central role in both the development of the pancreas and the regulation of insulin gene expression in the mature pancreatic β cell. A dominant-negative frameshift mutation in the IPF-l gene was identified in a single family and shown to cause pancreatic agenesis when homozygous and maturity-onset diabetes of the young (MODY) when heterozygous. We studied the role of IPF-1 in Caucasian diabetic and nondiabetic subjects from the United Kingdom. Three novel IPF-1 missense mutations (C18R, D76N, and R197H) were identified in patients with type 2 diabetes. Functional analyses of these mutations demonstrated decreased binding activity to the human insulin gene promoter and reduced activation of the insulin gene in response to hyperglycemia in the human β-cell line Nes2y. These mutations are present in 1% of the population and predisposed the subject to type 2 diabetes with a relative risk of 3.0. They were not highly penetrant MODY mutations, as there were nondiabetic mutation carriers 25‐53 years of age. We conclude that mutations in the IPF-1 gene may predispose to type 2 diabetes and are a rare cause of MODY and pancreatic agenesis, with the phenotype depending upon the severity of the mutation. J. Clin. Invest. 104:R33-R39 (1999).

Glucokinase mutations in a phenotypically selected multiethnic group of women with a history of gestational diabetes

Gestational diabetes mellitus (GDM) frequently provides the ®rst presentation of glucose intolerance in women with mutations in the glucokinase gene (GCK). Identifying such women during, or immediately after, their period of antenatal care is desirable since a molecular diagnosis of GCK de®ciency provides valuable prognostic information on the expected future patterns of glucose homeostasis of both mother and fetus [1,2]. However, molecular screening for GCK mutations is labour-intensive and currently impractical for universal use in GDM, and, as a result, preselection remains a necessary component of any molecular screening strategy. Ellard et al. recently described a set of clinical criteria, which when applied to a large cohort of GDM women, successfully preselected 15 European GDM women yielding a high prevalence (80%) of GCK mutations [2]. We have applied similar (but, in our case, purely biochemical) criteria to our local multiethnic antenatal population, namely: (i) mild fasting hyperglycaemia (5.5±8.0 mmol/l) in pregnancy; (ii) persisting mild fasting hyperglycaemia outside pregnancy (5.5±8.0 mmol/l); and (iii) an increment between the fasting and 2-h plasma glucose concentrations < 3.5 mmol/l during the 75-g OGTT postpartum. These criteria were met by 17 women of multiethnic origin (Table 1) with a median (interquartile range) age of 37.5 (34.0±40.3) years and a median parity of 2. Singlestranded conformational polymorphism analysis followed by direct sequencing was used to screen these women for GCK variants. Functional variants, previously reported, were detected in two of the 17 (12%) subjects: R403fsdelC (exon 9) and T228M (exon 7). In fact, neither subject would have been selected for screening according to the non-biochemical criteria included in previous studies [2] as neither had received insulin during pregnancy and only one had a family history of diabetes. R403fsdelC (exon 9) is a frameshift mutation and hence of probable functional signi®cance [2] and T228M (exon 7) is a missense mutation previously shown to cosegregate with Type 2 diabetes [3]. In addition, three novel and one previously reported intronic variants (IVS4nt±48insC, IVS9nt±18C®A, IVS9nt+49G®A, IVS9nt+8T®C), all considered neutral polymorphisms, were identi®ed in three South Asian subjects. The prevalence of functional GCK mutations detected in our study (12%) is higher than reported in some studies [4± 6], but considerably lower (P = 0.0001) than that reported by Ellard et al. [2]. There are three principal differences between the Ellard study [2] and ours. First, Ellard et al. applied additional non-biochemical preselection criteria, including family history of diabetes and insulin treatment during pregnancy. Given that the two subjects found in our study to have GCK-coding mutations would not have been preselected for molecular screening had the Ellard criteria been applied, we suggest that these non-biochemical criteria may be unnecessarily strict. Second, Ellard et al. screened only European women. It seems probable that the high prevalence and young onset of (non-GCK) Type 2 diabetes in Asian and Afro-Caribbean populations may reduce the relative proportion of GDM attributable to GCK mutations in these groups. Third, we note that our study subjects were fairly overweight which would be less typical of women with GCK mutations [1]. In summary, whilst a strong case can be made for molecular screening of the glucokinase gene in women with GDM, the most appropriate strategy remains to be determined. On current evidence, we recommend that GDM women with modestly elevated postpartum fasting glucose and a small glucose increment during an OGTT represent the most suitable group for genetic screening.