The molecular basis of pyruvate carboxylase deficiency: Mosaicism correlates with prolonged survival

Abstract

Pyruvate carboxylase (PC) deficiency (OMIM, 266150) is a rare autosomal recessive disease. The revised PC gene structure described in this report consists of 20 coding exons and four non-coding exons at the 5'-untranslated region (5'-UTR). The gene codes for three transcripts due to alternative splicing: variant 1 (NM_000920.3), variant 2 (NM_022172.2) and variant 3 (BC011617.2). PC deficiency is manifested by three clinical phenotypes -an infantile form (Type A), a neonatal form (Type B), and a benign form (Type C). We report the molecular basis for eight cases (one Type A, five Type B and two Type C) of PC deficiency. Eight novel complex mutations were identified representing different combinations of missense mutations, deletions, a splice site substitution and a nonsense mutation. The classical phenotypes (A, B and C) correlated poorly with clinical outcomes. Mosaicism was found in five cases (one Type A, three Type B and one Type C) and four of these cases had prolonged survival. Death in the fifth case resulted from unrelated medical complications. The discrepancy between the current findings and the existing classification system should be addressed to accommodate these new observations.

Characterization of the Distal Promoter of the Human Pyruvate Carboxylase Gene in Pancreatic Beta Cells

“…In contrast to our study, Wang et al [19] compared the 5′-UTR sequences of three human PC mRNA variants namely, variant 1 (NM_000920.3), 2 (NM_022172.2) and 3 (BC011617.2) deposited at the NCBI database to the genomic sequence of human PC gene and concluded that these variants are alternatively spliced from four 5′-UTR exons, i.e. UE1, UE2, UE3 and UE4, respectively, with the distal, middle and proximal promoters located immediately upstream of exons UE1, UE2 and UE4, respectively [19].…”

“…However, the regulatory regions of the PC gene that confer tissue-specific expression of PC in humans are not known. Recently, Wang et al [19] reported that unlike the rat and mouse PC genes, the human PC gene is transcribed from three promoters. Herein, we present evidence that similar to the rodent PC genes, the human PC gene is transcribed from two promoters.…”

Enzymes involved in l-lactate metabolism in humans

“…Two forms of human pyruvate carboxylase cDNAs have been identified in the liver that share the coding region but differ in their 5´ untranslated regions, suggesting that they are generated by alternative splicing of the primary transcript (Jitrapakdee, et al, 1996. A revision of the pyruvate carboxylase gene structure confirms the occurrence of alternative splicing that generates three transcripts and therefore three pyruvate carboxylase enzyme variants (Wang, et al, 2008). Kinetic analysis demonstrates that the recombinant human pyruvate carboxylase has the same properties as the native enzyme isolated from liver autopsy (Jitrapakdee, et al, 1996.…”

“…Tissue heterogeneity in the expression of the enzyme and increased residual enzyme activity in vivo have been offered as possible explanations. (Stern, et al, 1995, Wang, et al, 2008 Mosaicism has been found in most cases of pyruvate carboxylase deficiency with prolonged survival. (Wang, et al, 2008) A Recently, nuclear location of muscle fructose 1,6-bisphosphatase has been reported.…”

“…(Stern, et al, 1995, Wang, et al, 2008 Mosaicism has been found in most cases of pyruvate carboxylase deficiency with prolonged survival. (Wang, et al, 2008) A Recently, nuclear location of muscle fructose 1,6-bisphosphatase has been reported. (Mamczur, et al, 2012) The molecular structure of the human liver fructose 1,6-bisphosphatase has been determined.…”