Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate.
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.
Istituto di Genetica delle Popolazioni, Consiglio Nazionale delle Ricerche, Alghero, Italy. F.Gianfrancesco@igm.ss.cnr.it
Fernando
F
Gianfrancesco
Teresa
T
Esposito
Maria Neve
MN
Ombra
Paola
P
Forabosco
Giuseppe
G
Maninchedda
Mauro
M
Fattorini
Stefania
S
Casula
Simona
S
Vaccargiu
Giuseppina
G
Casu
Francesco
F
Cardia
Ivo
I
Deiana
Paola
P
Melis
Mario
M
Falchi
Mario
M
Pirastu
D000595:Amino Acid Sequence; D041322:Chromosomes, Human, Y; D016384:Consensus Sequence; D004272:DNA, Mitochondrial / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007669:Kidney Calculi / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*; D014527:Uric Acid / Q000378:metabolism* / Q000652:urine
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C475725:ZNF365 protein, human; D014527:Uric Acid