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

TY - JOUR

T1 - Identification of a Novel Gene and a Common Variant Associated with Uric Acid Nephrolithiasis in a Sardinian Genetic Isolate

AU - Gianfrancesco, Fernando

AU - Esposito, Teresa

AU - Ombra, Maria Neve

AU - Forabosco, Paola

AU - Maninchedda, Giuseppe

AU - Fattorini, Mauro

AU - Casula, Stefania

AU - Vaccargiu, Simona

AU - Casu, Giuseppina

AU - Cardia, Francesco

AU - Deiana, Ivo

AU - Melis, Paola

AU - Falchi, Mario

AU - Pirastu, Mario

PY - 2003/6

Y1 - 2003/6

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Chromosomes, Human, Y

KW - Consensus Sequence

KW - DNA, Mitochondrial

KW - DNA-Binding Proteins

KW - Founder Effect

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Italy

KW - Kidney Calculi

KW - Middle Aged

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Phylogeny

KW - Polymorphism, Single Nucleotide

KW - Protein Isoforms

KW - Protein Structure, Tertiary

KW - Sequence Homology, Amino Acid

KW - Transcription Factors

KW - Uric Acid

U2 - 10.1086/375628

DO - 10.1086/375628

M3 - Article

C2 - 12740763

SN - 0002-9297

VL - 72

SP - 1479

EP - 1491

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -