NEUROD1 mutation in an Italian patient with maturity onset diabetes of the young 6: a case report

Abstract

Background Maturity Onset Diabetes of the Young (MODY) is a monogenic, autosomal, dominant disease that results in beta-cells dysfunction with consequent hyperglycaemia. It represents a rare form of diabetes (1–2% of all the cases). Sulphonylureas (SUs) represent the first-line treatment for this form of diabetes mellitus. NEUROD1 is expressed by the nervous and the pancreatic tissues, and it is necessary for the proper development of beta cells. A neurogenic differentiation factor 1 (NEUROD1) gene mutation causes beta-cells dysfunction, inadequate insulin secretion, and hyperglycaemia (MODY 6). Case presentation We have documented a new missense mutation (p.Met114Leu c.340A > C) of the NEUROD1 gene, pathogenetic for diabetes mellitus, in a 48 years-old man affected by diabetes since the age of 25 and treated with insulin basal-bolus therapy. Unfortunately, an attempt to replace rapid insulin with dapagliflozin has failed. However, after the genetic diagnosis of MODY6 and treatment with SUs, he was otherwise able to suspend rapid insulin and close glucose monitoring. Interestingly, our patient had an early onset dilated cardiomyopathy, though no data about cardiac diseases in patients with MODY 6 are available. Conclusions Diagnostic criteria for MODY can overlap with other kinds of diabetes and most cases of genetic diabetes are still misdiagnosed as diabetes type 1 or 2. We encourage to suspect this disease in patients with a strong family history of diabetes, normal BMI, early-onset, and no autoimmunity. The appropriate therapy simplifies disease management and improves the quality of the patient’s life.

Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families

“…In maturity-onset diabetes of the youth (MODY), several studies demonstrated some NEUROD1 candidate mutations, including NEUROD1 p.Pro197His, p.Asp202Glu, p.Leu157Arg, and p.Arg103Pro ( Ang et al, 2016 ; Aǧladioǧlu et al, 2016 ; Szopa et al, 2016 ; Horikawa et al, 2018 ; Demirci et al, 2021 ). Recently, another heterozygous mutation, NEUROD1 p.Met114Leu (c.340A > C), was reported in an Italian patient with MODY6 ( Brodosi et al, 2021 ). This variant is predicted to be pathogenic based on many prediction tools and was later confirmed in a French family ( Bouillet et al, 2020 ).…”

Diabetes Mellitus Diagnosed in Childhood and Adolescence With Negative Autoimmunity: Results of Genetic Investigation

“…Over the next 20 years, NEUROD1 variants have been reported as causative of diabetes in almost 20 families ( 22 ). More recently, several other cases of MODY6 have been diagnosed all around the world, mainly due to widespread use of NGS technology ( 23 – 28 ). NEUROD1 is a transcription factor that is implicated in early development and differentiation of pancreatic α- and β-cells ( 29 ) and in activation of insulin gene transcription ( 30 ).…”

“…Recently, Brodosi et al. described a NEUROD1 variant in a 48-year-old patient diagnosed with MODY at the age of 25 ( 28 ). Making the right genetic diagnosis of MODY6 is important to start adequate treatment as soon as possible to prevent chronic hyperglycemia.…”

Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development

“…NEUROD1 inactivation during the differentiation of human embryonic stem cells causes neonatal diabetes mellitus and defective β-cell function ( Romer et al, 2019 ). Early-onset diabetes due to homozygous or heterozygous NEUROD1 mutations have also been reported in human patients ( Kristinsson et al, 2001 ; Liu et al, 2007 ; Gonsorčíková et al, 2008 ; Rubio-Cabezas et al, 2010 ; Chapla et al, 2015 ; Bouillet et al, 2020 ; Brodosi et al, 2021 ), thus NEUROD1 is associated with maturity-onset diabetes of the young (MODY), i.e., MODY6 ( Horikawa and Enya, 2019 ). Heterozygous NEUROD1 mutations are also linked to autosomal dominant type 2 diabetes ( Malecki et al, 1999 , 2003 ).…”

“…The conserved bHLH domain is located at aa101–153. Mutations within the region coding bHLH, including NEUROD1 R103P , NEUROD1 E111K and NEUROD1 M114L , probably abolish the binding of the mutant proteins to the promoters of target genes ( Kristinsson et al, 2001 ; Szopa et al, 2016 ; Brodosi et al, 2021 ). These mutations are associated to MODY.…”