Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout

Abstract

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K—a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type—has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397–405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations—c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update

“…Hyperuricemia and gout pathology has often been shown to be related to genetic predisposition [30] and to be affected by SNPs in many of the genes encoding urate transporters [87,88]. Among these, especially SNPs of ABCG2 have been highly associated with pediatric-onset hyperuricemia and early-onset gout [89][90][91][92][93]. These polymorphisms are summarized and organized in Table 1 according to the standard nomenclature rules for molecular diagnostics [94].…”

“…In contrast, the Q141K and Q126X polymorphisms are enriched in Japanese populations, whereas in Caucasians, Q141K is not as common and Q126X is virtually absent [97]. Our understanding of the genetic variations in the ABCG2 sequence associated with hyperuricemia and gout is still incomplete, as evidenced by the recent discovery of less common polymorphisms previously unrecognized or not studied in the context of hyperuricemia and gout [89,90,95,100]. Two of these newly identified rare polymorphisms have been recently described in a case report of a 12-year-old Czech girl of Roma ethnicity with chronic asymptomatic pediatric-onset of hyperuricemia [89].…”

“…Our understanding of the genetic variations in the ABCG2 sequence associated with hyperuricemia and gout is still incomplete, as evidenced by the recent discovery of less common polymorphisms previously unrecognized or not studied in the context of hyperuricemia and gout [89,90,95,100]. Two of these newly identified rare polymorphisms have been recently described in a case report of a 12-year-old Czech girl of Roma ethnicity with chronic asymptomatic pediatric-onset of hyperuricemia [89]. In this regard, several rare diseases have been found to occur primarily or exclusively in individuals of Roma ethnicity, and many of the mutations underlying these diseases have been recently discovered, such as for Charcot-Marie tooth disease types 4D and 4G [101,102], the congenital cataract facial dysmorphism neuropathy [103], the Gitelman syndrome [104], and the Galactokinase deficiency [105].…”

“…In contrast, the M131I mutation was translated to a full-length protein with no impairments in N-glycosylation at residue N596 and normal membrane localization. However, the urate transport capabilities of the M131I mutant were reduced to <15% of wildtype levels [89]. M131 itself was found to be a highly conserved residue that is localized close to the Q-loop within the nucleotide-binding domain of ABCG2 (Figure 1).…”

Aboriginal Bacterial Flora in the Uricase-Deficient Rat Gut is Not the Main Factor Affecting Serum Uric Acid

“…By hydrolyzing ATP, ABCG2 can actively Evidence-Based Complementary and Alternative Medicine pump urate to renal tubular lumen [22] or intestinal fluids [23]. ABCG2 deficiency was proved to be a key factor to increase SUA in both human [24] and mice [25]. e two substrates (ciprofloxacin and urate) could compete for the function of ABCG2 and increase the SUA level (Figure 1(d)).…”