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  • In analyzed alleles in this


    In 3/11 analyzed North American in this study, the c.472C>T missense variant was detected. This variant was previously reported in Malaysian, French, Indian and Pakistani patients (Bhai et al., 2018; Ijaz et al., 2017; Lebigot et al., 2015; Moey et al., 2018; Ngu et al., 2014) who were homozygous and compound heterozygous. In the Punjab Province, Pakistan, there appears to be a founder effect acting on this variant (Ijaz et al., 2017). In addition, the c.472C>T variant has been observed in a database in 6 South Asian, 2 Finnish European and 1 Ashkenazi Jewish individuals in heterozygosis, with a frequency of 0.00003668 (gnomAD database). The c.472C>T variant was detected in two patients, one homozygous and one compound heterozygous. Both patients appear to have this allele in linkage disequilibrium with the same haplotype (#1). Thus, this may indicate that a founder effect is acting in this population. Nevertheless, it is not established whether the variant c.472C > T has a single origin and has spread between different populations or has several different origins. We believe that the first alternative is more reasonable because exon 5 is lowly polymorphic (Fig. 2) and highly conserved in related species. The variants c.958G>A and c.986T>C were present in 5/11 and 3/11 of the alleles detected. Three homozygotes presented the c.958G>A allele, and one of them had consanguineous parents, whereas the variant c.986T>C was detected in one homozygous patient and another compound heterozygous patient. The c.958G>A variant occurs in a hot spot variant site in exon 8. This region presents the c.966delC pathogenic variant (Herzog et al., 1999) and the most frequent pathogenic variant in FBPase deficiency patients, c.959dupG, which was found in Japanese, European and Chinese patients (Herzog et al., 2001; Kikawa et al., 1997; Lebigot et al., 2015; Lu et al., 2017; Xu et al., 2014). The sequence analysis demonstrated that it is a C/G rich quasi-palindrome that favors the occurrence of indel variants (Kikawa et al., 1997). For this reason, it is suggested that variants in this site have had many origins and there is not only a founder effect acting about on these alleles. However, the c.958G>A variant is in linkage disequilibrium with haplotype #2, while c.986T>C presents one different haplotype (#3). These polymorphisms were present in a haplotype associated with the deletion c.-24-26_170+5192del in Armenian and Turkish populations (Santer et al., 2016). Excluding the pathogenic variants, the frequency of these haplotypes (#2, #3) in the world's population is approximately 0.3426 and 0.3405, respectively. These results indicate that the variants c.958G>A and c.986T>C arose in the RS and remains in a population with low outbreeding favoring the emergence of homozygous to the same allele. This study presents a summary of clinical and genetic data of 6 patients from Southern Brazil, confirming the FBPase deficiency diagnosis in all of them. The genetic analyses were performed by NGS with the IonTorrent platform, and two novel variants were found in FBP1. The data suggest that the novel variants appeared once and spread throughout the Southern Brazilian population by an endogamy effect.
    Conclusion In summary, this study presents the first genetic analysis of Brazilian patients with FBPase deficiency. Surprisingly, a small number of different variants was found despite the apparently low consanguinity rate, which suggests that c.958G>A and c.986T>C are the most frequent pathogenic variants of FBP1 in the region of Southern Brazil. The following are the supplementary data related to this article.
    Introduction Fructose-1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC, FBPase) catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate, in the presence of divalent metal ions like magnesium, manganese, cobalt or zinc [1], [2]. Vertebrate FBPases are inhibited competitively by fructose-2,6-bisphosphate, and allosterically by adenosine monophosphate (AMP) [3], [4].