Molecular Analysis of the HGD Gene in 9 Families With Alkaptonuric Ochronosis in Iran and Identification of Two Novel Variants.

objectivesAlkaptonuria (AKU) (MIM number 203500) or homogentisic acid oxidase deficiency is a metabolic autosomal recessive disorder caused by mutations in the homogentisate 1, 2-dioxygenase (HGD) (MIM number 607474) gene. The HGD is located on chromosome 3q13 with 14 exons, and encodes the homogentisate 1, 2-dioxygenase enzyme, which is composed of 445 amino acids. Although AKU was first described more than 120 years ago, we lack studies investigating its mutational spectrum in Iran. MATERIALS AND

resultsThis study aimed to investigate the spectrum of homogenetic gene mutations in patients diagnosed with Ochronosis Alkaptonuria in Ardabil, Iran. To achieve this, all individuals affected by this disease, totaling 23 individuals, whose affliction with Ochronosis Alkaptonuria had previously been definitively confirmed, were enrolled in the study. Sanger sequencing identified five unique variants in the HGD gene (NM_000187.4), all of which were homozygous variants. Two of the variants (c.113delA and c.342+5G>A) were novel and have not been reported in variant databases, including gnomAD, ClinVar, and HGMD. Other identified variants were c.175delA, c.334T>G, and c.680T>C, which have been previously reported in variant databases.

conclusionIn this study, the mutational spectrum of alkaptonuric ochronosis was investigated in Iran. The HGD gene is a well-studied gene, and hundreds of variants responsible for alkaptonuria have been reported to date. However, we found two novel variants that have not been reported in previous studies.