ABSTRACT
AIM: Permanent neonatal diabetes mellitus (PNDM) is a rare monogenic form of non-autoimmune diabetes. Genetic defects have been identified inâ¼60% of cases, with mutations in ABCC8, KCNJ11 and INS being the most frequent causes of PNDM. Recognition of genetic subtypes strongly impacts on both patients' care and family counseling. This study aimed to identify the genetic aetiology of PNDM in a diabetic girl born of consanguineous parents. METHODS: DNA samples from both the proband and her non-diabetic parents were analyzed for homozygosity mapping, using Illumina Infinium 660K SNP microarrays, focusing on the runs of homozygosity (ROHs) detected only in the patient. Standard Sanger sequencing of candidate genes (MNX1 and GATA6) present in the ROHs was subsequently performed, as well as expression analyses on human embryonic and adult pancreatic islet samples. RESULTS: A putative causal homozygous mutation in the transcription factor gene MNX1 (c.816C>A/p.Phe272Leu) was identified in the PNDM patient, who was clinically diagnosed as a typical case of PNDM with no developmental pancreatic defects or other clinical features. The probable deleterious mutation was located within the MNX1 homeodomain helix 2 that is highly conserved between species. In human embryonic pancreatic islet samples, it has been shown that MNX1 expression is significantly enriched in pancreatic epithelium compared with mesenchyme, suggesting a role for MNX1 in human pancreatic beta-cell development. CONCLUSION: This study found a new putative cause of PNDM in a consanguineous family. Replication in other cohorts would help to clarify the clinical spectrum of MNX1 mutations in PNDM patients.
