Abstract

Shadia A. Fathy, Amina M. Medhat, Mohamed A. El Sawy, Mona H. El Samahy Eman M.-Elsayed and Osama K. Zaki*

ABSTRACT

The hepatocyte nuclear factor 1? (HFN1?) is a member of the nuclear receptor superfamily that regulates genes which play a critical role in glucose metabolism. A genome-wide association studies showed that mutations in the human HNF1? gene cause a maturity onset diabetes of young (MODY3). Accordingly, HNF1-? mutants caused -cell dysfunction in MODY3 is caused by loss of function mechanisms like reduced DNA binding, impaired transcriptional activation, and defects in subcellular localization (Ghosal et al., 2012). This study was done to determine genotype characteristics of eight Egyptian patients with HNF1? variants caused MODY3 type and to examine the influence of HNF1? mutation type, or location on clinical phenotypes. Blood of eight child Egyptian patients (three females and five males) aged 13.6 years ± 6.18, and their age at diagnosis was 5.5 years ±3.4 were analysed to detect the possible mutations of the HNF1-? gene. Their clinical investigations indicating that, FBS was 179 mg/dl ±54.2, PPS was 265.6 mg/dl ± 74.7, C-peptide was 2.2 pmol ±0.38, HbA1c ? was 10.4% ±2.9, HOMA-IR (0.96 ± 0.366) and BMI was 26.26± 5.79. Genomic DNA was extracted then polymerase chain reaction and DNA sequence analysis were performed accordingly for 10 entire coding exons with specific primer sets. A total of 22 mutations prevailed; 4 were previously known mutations (I27L, E90V, E105G and S487N), in addition to 8 silent mutations (G288G, P379P, L459L, G323G, L341L, V344V, L369L and P488P) were detected. Frameshift mutation (c.1189delT23) caused a silent mutation (S388S) and created a stop codon after 23 amino acid producing a truncated protein with 411 amino acids (M412X). The deduced protein missed 190 amino acids from carboxylic terminal. Moreover, nine missense novel mutations were first identified among Egyptian patients; all of them were located in Exon 5 (P325D, P334S, V342G, T346P, P347S, S359R, S361N, L362Q, L363W). It was observed that maximum number of variations were existed in exon 5 of HNF1-?, which may be referred to “Mutational Hotspot” as previously reported by (Ghosal et al., (2012). The position of the mutation relative to the functional domains of HNF1-?, obesity state and HOMA-IR also plays a role in the severity of MODY3 disease.