Nucleotide Variants of the BH4 Biosynthesis Pathway Gene GCH1 and the Risk of Orofacial Clefts

Abstract

A deficiency of GTP cyclohydrolase, encoded by the GCH1 gene, results in two neurological diseases: hyperphenylalaninaemia type HPABH4B and DOPA-responsive dystonia. Genes involved in neurotransmitter metabolism and motor systems may contribute to palatogenesis. The purpose of the study was to analyse polymorphic variants of the GCH1 gene as risk factors for non-syndromic cleft lip with or without cleft palate (NSCL/P). Genotyping of nine polymorphisms was conducted in a group of 281 NSCL/P patients and 574 controls. The GCH1 variant rs17128077 was associated with a 1.7-fold higher risk for NSCL/P (95 %CI = 1.224–2.325; p = 0.001). We also found a significant correlation between the rs8004018 and rs17128050 variants and an increased risk of oral clefts (p trend = 0.003 and 0.004, respectively). The best evidence of the global haplotype association was observed for rs17128050 and rs8004018 (p corr = 0.0152). This study demonstrates that the risk of NSCL/P is associated with variants of the GCH1 gene related to BH4 metabolism and provides some evidence of the relationships between morphological/functional shifts in the central nervous system and orofacial clefts.

Polymorphic Variants of BH4 Pathway Genes and Isolated Hypospadias Risk

“…A study conducted by Lupo and colleagues (16) suggested a link between haplotypes of GCH1 gene and ab- normal neural tube closure in the USA. In our previous study, we found a significant association between the GCH1 rs17128077, rs8004018 and rs17128050 variants with an in-creased risk for cleft lip with or without cleft palate (9). The correlation with single polymorphic variants was confirmed at the haplotype level (9).…”

“…In our previous study, we found a significant association between the GCH1 rs17128077, rs8004018 and rs17128050 variants with an in-creased risk for cleft lip with or without cleft palate (9). The correlation with single polymorphic variants was confirmed at the haplotype level (9). The investigated variants of the GCH1 were not found to be involved in the pathogenesis of HS.…”

“…Five SNPs in GCH1 and PAH, previously detected to be in association with orofacial clefts risk in the Polish population (9,17), as well as rs2191349 of the AGMO-DGKB loci were evaluated in this study (Table 1). The genotyping was carried out by high-resolution melting curve analysis (HRM) on the Light Cycler 480 system (Table 2).…”

“…HS is associated with a high rate of extra urogenital anomalies, e.g., congenital heart defects, orofacial clefts and spina bifida (13)(14)(15), leading to the anticipation that there may be a partly shared genetic background for these congenital anomalies. Polymorphic variants of GCH1 are associated with the pathogenesis of spina bifida (16) and orofacial clefts (9). The involvement of the PAHgen in the etiology of orofacial clefts was reported in the Polish population (17).…”

“…BH4, a metabolite structurally related to riboflavin and folic acid by sharing the common pterin backbone, is synthesized de novo from guanosine triphosphate (GTP) through the catalysis of three enzymatic reactions by GTP cyclohydrolase (GTPCH, EC 3.5.4.16; rate-limiting step), 6-pyruvoytetrahydrobiopterin synthase, and sepiapterin reductase (8). GTPCH deficiency, due to loss of function mutations in the GCH1 gene, results in neurological disorders (7)(8)(9). Urine profiles of pterin compounds have the potential to become predictive biomarkers of bladder cancer (10).…”