Endocrine Abstracts

Background and aims: Most children with permanent neonatal diabetes (PNDM) have heterozygous mutations in KCNJ11, ABCC8 or INS genes if they have unrelated parents. Although homozygous mutations in GCK and ABCC8 have been described in the offspring of consanguineous parents the genetic aetiology in most of these cases remains unknown. We hypothesised that homozygous mutations in the INS gene could cause PNDM in these patients.

Materials and methods: We screened INS, GCK, KCNJ11 and ABCC8 by direct sequencing in 25 patients of consanguineous descent with non-syndromic PNDM and used Multiplex Ligation-dependent Probe Amplification (MLPA) to test for INS deletions. Data are given in median (interquartile range).

Results: We identified five novel homozygous mutations in INS in 8 probands (32%): c.−331C>G (n=3), M1I (n=2), Q62X (n=1), IVS2-15G>A (n=1), and M1_Q62del (n=1). These variants were not found in control population subjects. In addition, there were 9 mutations in the known PNDM-associated genes: 5 homozygous GCK mutations (20%), 2 homozygous ABCC8 mutations (8%) and 2 heterozygous KCNJ11 mutations (8%).

Compared to 42 heterozygous INS mutation carriers, patients with a homozygous INS mutation were born with a more severe intrauterine growth restriction (birth weight adjusted for gestational age: −3.54 (−3.95, −3.28) vs −1.55 (−2.36, −0.74) SDS, P<0.0005) and diabetes was diagnosed earlier (age at diagnosis in weeks: 0.86 (0.1, 3.4) vs 10.8 (9.0, 21.7), P=0.005). In contrast, they were phenotypically undistinguishable from GCK-PNDM patients (birth weight −3.33 (−3.50, −2.80) SDS, P=0.30; age at diagnosis 1.0 (1.0, 8.0) weeks, P=0.46).

Conclusions: We have shown that homozygous mutations in INS are a novel cause of PNDM and are the commonest cause (32%) of PNDM in offspring of consanguineous parents. The mutations result in reduced insulin production by affecting the promoter, translation or the protein sequence in contrast to the heterozygous mutations that result in misfolding of the insulin gene and destruction of the beta-cells.