Inheritance of HNF1a and GCK Mutations in a Family With MODY
Inheritance of HNF1a and GCK Mutations in a Family With MODY
This study has identified the novel c.-154_-160dupTGGGGGT HNF1A mutation in two different MODY 3 families. In addition, and to the best of our knowledge, this is the first report of co-inheritance of HNF1A and GCK mutations in two patients (c.-154_-160dupTGGGGGT and p.Y61X, respectively). Mutation c.-154_-160dup is located in the 5' UTR regulatory region of the HNF1A gene. The pathogenicity of this variation is supported by several lines of evidence. Firstly, it affects the characteristics of this region, such as length, thermal stability, GC content, translation start-site context and secondary structure, which are known to influence mRNA translation. In fact, in silico analysis predicted this mutation disrupting the mRNA secondary structure, thus supporting its potential to impair the binding of regulatory translation factors which could alter HNF1A gene expression. Secondly, the duplication is located in a highly conserved region among mammals (humans, rats and mice), indicating its functional relevance. Thirdly, other mutations located in the 5' UTR of the HNF1A gene have been suggested to be pathogenic. Fourthly, the mutation co-segregated in a dominant fashion with MODY 3 phenotypes in two different families. In spite of all this evidence, further functional studies are required to confirm the pathogenicity of this novel HNF1A mutation.
The second sequence variation identified in this study, GCK p.Y61X, is likely to be a null mutation because the premature termination codon could activate the nonsense-mediated mRNA decay mechanism, followed by a complete loss of GCK enzymatic activity from the mutant allele. In addition, p.Y61X has also been previously reported in the homozygous state in a patient with permanent neonatal diabetes mellitus and in the heterozygous state in six affected members of a Spanish MODY 2 family. Finally, the mutation co-segregated with the disease and was absent in 100 control individuals, further supporting its pathogenicity.
We detected co-inheritance of GCK and HNF1A mutations associated with a typical MODY 3 phenotype in an adult patient (family-1, subject II:9). In contrast, a younger patient with the same genotype (patient III:1) showed only impaired fasting glucose (IFG) during the last follow-up, probably due to a shorter disease evolution. Therefore, the presence of a second MODY mutation apparently does not modify the MODY 3 phenotype. We may speculate that the progressive β-cell function failure caused by HNF1A mutations, which eventually impairs response to physiological stimuli, such as glucose, is more limiting than the alteration of the glucose set point for insulin secretion originated by GCK mutations, resulting in a dominant effect. A clinical follow-up of all these patients is required to firmly establish the MODY 2–3 phenotypic features. The three youngest carriers of the novel HNF1A mutation were asymptomatic (III:3) or presented IFG (III:4 and III:5) at the time of the study (Table 1). Usually, MODY 3 is a postpubertal disease; therefore, these subjects could be at either a presymptomatic or an early disease stage.
It is generally assumed that only one gene is involved in MODY. Our study illustrates that given the prevalence of the most common MODY type (MODY 2 and MODY 3), some patients may carry mutations in both the GCK and HNF1A genes, leading to three possible different MODY genotypes in the same family. This fact should be considered for accurate diagnoses, management, treatment and counselling of this type of monogenic diabetes.
Discussion
This study has identified the novel c.-154_-160dupTGGGGGT HNF1A mutation in two different MODY 3 families. In addition, and to the best of our knowledge, this is the first report of co-inheritance of HNF1A and GCK mutations in two patients (c.-154_-160dupTGGGGGT and p.Y61X, respectively). Mutation c.-154_-160dup is located in the 5' UTR regulatory region of the HNF1A gene. The pathogenicity of this variation is supported by several lines of evidence. Firstly, it affects the characteristics of this region, such as length, thermal stability, GC content, translation start-site context and secondary structure, which are known to influence mRNA translation. In fact, in silico analysis predicted this mutation disrupting the mRNA secondary structure, thus supporting its potential to impair the binding of regulatory translation factors which could alter HNF1A gene expression. Secondly, the duplication is located in a highly conserved region among mammals (humans, rats and mice), indicating its functional relevance. Thirdly, other mutations located in the 5' UTR of the HNF1A gene have been suggested to be pathogenic. Fourthly, the mutation co-segregated in a dominant fashion with MODY 3 phenotypes in two different families. In spite of all this evidence, further functional studies are required to confirm the pathogenicity of this novel HNF1A mutation.
The second sequence variation identified in this study, GCK p.Y61X, is likely to be a null mutation because the premature termination codon could activate the nonsense-mediated mRNA decay mechanism, followed by a complete loss of GCK enzymatic activity from the mutant allele. In addition, p.Y61X has also been previously reported in the homozygous state in a patient with permanent neonatal diabetes mellitus and in the heterozygous state in six affected members of a Spanish MODY 2 family. Finally, the mutation co-segregated with the disease and was absent in 100 control individuals, further supporting its pathogenicity.
We detected co-inheritance of GCK and HNF1A mutations associated with a typical MODY 3 phenotype in an adult patient (family-1, subject II:9). In contrast, a younger patient with the same genotype (patient III:1) showed only impaired fasting glucose (IFG) during the last follow-up, probably due to a shorter disease evolution. Therefore, the presence of a second MODY mutation apparently does not modify the MODY 3 phenotype. We may speculate that the progressive β-cell function failure caused by HNF1A mutations, which eventually impairs response to physiological stimuli, such as glucose, is more limiting than the alteration of the glucose set point for insulin secretion originated by GCK mutations, resulting in a dominant effect. A clinical follow-up of all these patients is required to firmly establish the MODY 2–3 phenotypic features. The three youngest carriers of the novel HNF1A mutation were asymptomatic (III:3) or presented IFG (III:4 and III:5) at the time of the study (Table 1). Usually, MODY 3 is a postpubertal disease; therefore, these subjects could be at either a presymptomatic or an early disease stage.
It is generally assumed that only one gene is involved in MODY. Our study illustrates that given the prevalence of the most common MODY type (MODY 2 and MODY 3), some patients may carry mutations in both the GCK and HNF1A genes, leading to three possible different MODY genotypes in the same family. This fact should be considered for accurate diagnoses, management, treatment and counselling of this type of monogenic diabetes.