Allelic spectrum of formiminotransferase‐cyclodeaminase gene variants in individuals with formiminoglutamic aciduria

Abstract

BackgroundElevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase‐cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD.MethodsIn order to further understanding about the molecular alterations that contribute to FIGLU‐uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion.ResultsIndividuals tested had biallelic loss‐of‐function variants in protein‐coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in‐frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A).ConclusionWe observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.

Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening

“…Between 2009-2015 there were 707,785 births in the state of New Jersey, and 12 confirmed FTCD deficiency cases for an overall incidence of 1 in 58,982. This is comparable with the previously reported rate of 1 in 46,000 among infants born in Michigan (Majumdar et al 2017). Among the 12 FTCD deficiency patients born in New Jersey, 5 were evaluated at the Children’s Hospital of Philadelphia (CHOP) and were therefore included in this analysis.…”

“…Formiminoglutamic aciduria (FIGLU-uria or FTCD deficiency) is one of five known inborn errors of folate metabolism. It is the second most common folate disorder, with a reported incidence of approximately 1:46,000 (Majumdar et al 2017). The deficiency is due to mutations in the FTCD -encoded bifunctional protein, which is required for histidine metabolism.…”

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh

“…Severe forms have been reported to cause mental and physical retardation, anemia, and elevated serum folate, while less severe cases have been reported to have developmental delay and elevated levels of FIGLU in urine [30], which accumulates due to FTCD deficiency ( Fig 4 ). Recent work has demonstrated that individuals homozygous for putative loss-of-function mutations in FTCD have clearly detectable levels of FIGLU in urine in the absence of histidine loading (which is normally very low or undetectable), in the range of 5 to 195 mmol per mol creatinine [43].…”

“…To assess the potential impact of rs61735836 on urine FIGLU, we measured FIGLU in baseline urine samples for 60 of our HEALS participants (20 for each of the three rs61735836 genotype categories) using tandem mass spectrometry in the laboratory of Dr. Devin Oglesbee as described previously [43]. We observed no evidence for elevated FIGLU among carriers or non-carriers of the G allele, with no participant having a FIGLU >0.25 mmol/mol creatinine ( S9 Fig ).…”

Exploring the mechanism of Shendi Bushen capsule in anti-renal fibrosis using metabolomics theory and network analysis

“…29 Formiminoglutamic acid is a compound of glutamic acid and its derivatives, which is the degradation product of l -histidine. 30 Both are involved in the synthesis and degradation of histidine in histamine metabolism. Histidine is an anti-inflammatory and antioxidant factor.…”