Identification of a Novel Gene and a Common Variant Associated with Uric Acid Nephrolithiasis in a Sardinian Genetic Isolate

Abstract

Uric acid nephrolithiasis (UAN) is a common disease with an established genetic component that presents a complex mode of inheritance. While studying an ancient founder population in Talana, a village in Sardinia, we recently identified a susceptibility locus of approximately 2.5 cM for UAN on 10q21-q22 in a relatively small sample that was carefully selected through genealogical information. To refine the critical region and to identify the susceptibility gene, we extended our analysis to severely affected subjects from the same village. We confirm the involvement of this region in UAN through identical-by-descent sharing and autozygosity mapping, and we refine the critical region to an interval of approximately 67 kb associated with UAN by linkage-disequilibrium mapping. After inspecting the genomic sequences available in public databases, we determined that a novel gene overlaps this interval. This gene is divided into 15 exons, spanning a region of approximately 300 kb and generating at least four different proteins (407, 333, 462, and 216 amino acids). Interestingly, the last isoform was completely included in the 67-kb associated interval. Computer-assisted analysis of this isoform revealed at least one membrane-spanning domain and several N- and O-glycosylation consensus sites at N-termini, suggesting that it could be an integral membrane protein. Mutational analysis shows that a coding nucleotide variant (Ala62Thr), causing a missense in exon 12, is in strong association with UAN (P=.0051). Moreover, Ala62Thr modifies predicted protein secondary structure, suggesting that it may have a role in UAN etiology. The present study underscores the value of our small, genealogically well-characterized, isolated population as a model for the identification of susceptibility genes underlying complex diseases. Indeed, using a relatively small sample of affected and unaffected subjects, we identified a candidate gene for multifactorial UAN.

A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth

“…Among these, one clone was identical to human KIAA0844 (accession number AB020651), for which the mouse counterpart gene has been reported to show high expression in the brain. 28,29 The open-reading frame encoded a putative 407 amino-acid protein, without significant homology to any other known protein that was predicted to have one C 2 H 2 zinc-finger domain (amino acids 26-51) and several stretches of amino acids that could possibly form coiled-coil domains (amino acids 169-297) ( Figure 1a). Therefore, we designated this protein as DISC1-Binding Zinc-finger protein (DBZ).…”

Genetic regulation of bone mass and susceptibility to osteoporosis

“…A disadvantage of linkage studies in complex disease is that they have a relatively low statistical power to detect genes that have modest effects on the trait of interest, even when sample sizes of several thousand are used (Altmuller et al 2001). Reflecting this fact, linkage studies of outbred human populations have so far met with limited success in terms of identification of genes that predispose to osteoporosis, whereas studies of isolated populations have been more successful in identifying genetic variants that predispose to osteoporosis (Styrkarsdottir et al 2003) and other complex diseases (Gianfrancesco et al 2003;Gretarsdottir et al 2003).…”

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands

“…13 The use of isolated populations is a powerful approach in the search for disease genes and has facilitated the identification of candidate chromosome regions involved in monogenic diseases 14 and in some complex diseases, for example, uric acid nephrolithiasis. 15 Isolated populations have also been used to study susceptibility genes for autism-spectrum disorders in Finland, and evidence for a susceptibility locus was found on chromosome 3q25-27, 16 in addition to evidence for risk loci for Asperger's syndrome on 1q21-22, 3p14-24, and 13q31-33. 17 We used the isolated population of the Faroe Islands to search for susceptibility genes of autism.…”