Study points to new genetic model for disease

LONDON — A novel mode of inheritance has been discovered that may prompt scientists to re-evaluate the genetic basis of disease. In 21 September Science, Nico Katsanis and colleagues, from the Baylor College of Medicine (BCM), Houston; Institute of Child Health, London and the Simon Fraser University, British Columbia have shown that the well-defined boundaries between classical Mendelian traits and complex traits may, in fact, be blurred.Katsanis et al. found that mutations in three alleles from two genes combine to result in a rare genetic disorder called Bardet–Biedel syndrome (BBS) — previously thought to have been caused by a single gene effect."We have known that genes interact for a long time, but we have only looked at both ends of the scale, that is, from a one gene-one disease model to a complex mode of inheritance which involves several genes plus environmental factors," said Katsanis."But we have learnt something new about the way a gene can cause disease and these findings seem to show there is in fact a continuous scale that bridges the gap between classical Mendelian and complex traits. This reduces complex questions to more simple models."Genetic diseases are often divided into Mendelian and multifactorial (or complex) traits. In diseases caused by classical Mendelian inheritance — such as cystic fibrosis — a change in phenotype arises from mutations in one (dominant) or both copies (recessive) of a single gene. On the other hand, most common diseases in the developed world — such as hypertension, diabetes or asthma — are multifactorial in nature and are caused by mutations in more than one gene, together with interactions from environmental factors.But, there is a further degree of complexity to Mendelian disorders as a phenomenon called locus heterogeneity arises when single mutations in different genes result in a similar or identical phenotype.A typical example of a rare, genetically heterogeneous disorder is BBS. Patients with the disorder have a complex and variable phenotype that includes pigmentary retinal dystrophy, polydactyly, central obesity, hypogonadism, learning difficulties and renal dysplasia — and in some cases, asthma and diabetes. Genetic studies in BBS in families led to the hypothesis that the syndrome was inherited in an autosomal recessive manner. Six candidate loci (BBS 1-6) had been identified, with some evidence for a second locus being involved.When they analyzed one locus, BBS6, in 163 patients, they identified eight pedigrees that had mutations, with seven out of eight having only a single mutant BBS6 allele. But, they also identified one pedigree in which both the affected and unaffected sibs carried a single mutant allele (A242S) in BBS6, but the affected sibs also possessed homozygosity by descent across the BBS2 locus. This could be caused by two mechanisms: either the A242S allele is a rare polymorphism, or BBS arises from inheritance of mutations in more than one gene.Since that study, the BBS6 and BBS2 genes had been cloned. BBS6 encodes a putative chaperonin whereas BBS2 encodes a protein of unknown function. This gave the researchers the opportunity to test in more detail whether BBS arises from multiallelic inheritance by analyzing the same study cohort for coding sequence alterations in BBS2. After deducing the exon–intron structure of BBS2, they amplified and sequenced each of the 17 exons of this gene in the entire patient cohort.They identified six pedigrees where two independent mutations segregated with the disease. But despite full sequence coverage of the BBS2 open reading frame and exon/intron boundaries, only a single mutant allele was identified in the eight pedigrees. The authors reasoned that there were four possible explanations for this result: (1) the single alleles found may not be pathogenic but were rare polymorphisms; (2) they were detecting rare BBS2 carriers by chance; (3) a second mutation was present but it was within intronic or regulatory regions, or was undetected by the sequence analysis because of deletions of the whole or part of the gene; or (4) additional mutations lie in another gene and it is the combination of mutant alleles at two or more loci that causes the BBS phenotype.The researchers argued that the first two reasons were unlikely. To see whether there was an unidentified deletion or another mutation existed in other regions of the BBS2 gene, they genotyped several microsatellites around BBS2 and tested whether each product was consistent with linkage to BBS2. Of the six pedigrees that provided sufficient information, one showed consistent linkage with BBS2 whereas five could be genetically excluded from BBS2.But when they genotyped polymorphic microsatellites from all the BBS loci to monitor the segregation of the parental chromosomes from these five pedigrees, this suggested that three out of five pedigrees might harbor BSS1 mutations, one mapped to BBS3 and the other was assigned to BBS6. This suggested that mutations at more than one loci might be present in BBS patients.To test this hypothesis, they integrated and expanded all the sequence data from BBS2 and BBS6 to obtain a complete scan of the ORFs of both genes and constructed detailed haplotypes across both genomic regions. They found that among the 19 pedigrees that had mutations in both copies of BBS6, at least nine families also had an additional mutation in a single copy of BBS2. The same was true for BBS6 — of the eight pedigrees that had mutations in both copies of this gene; three also harbored a BBS2 mutation.From this, the authors proposed a model of triallelic inheritance, in which three mutant alleles segregate with the disorder. Although there is evidence for inheritance of multiple alleles in other disorders, such as retinitis pigmentosa, the only other example of a triallelic requirement for a Mendelian trait is Charcot–Marie–Tooth neuropathy type 1A. But, this disorder is a dominant trait, making triallelic inheritance in BBS a novel model where a third allele is required for the disease to manifest itself.James Lupski, Cullen Professor of Molecular and Human Genetics and Professor of Pediatrics at BCM and co–author of the study, hopes that this model of inheritance might help researchers to look at complex traits in a different way, which may help them in future — and in previous — genetic studies. "People thought of inheritance in complex traits in terms of biallelic inheritance, that is, does a particular mutation segregate with a certain trait? If it didn't, then they were excluded from being a candidate," he said."But just as research into cystic fibrosis taught us about positional cloning in single gene disorders, this study may teach us about positional cloning in complex models by making us think about complex traits in a different way.""It may also make researchers go back to their research on other recessive disorders, look at any spurious data they may have had and reassess these findings by thinking about a triallelic rather than the conventional biallelic mode of inheritance," he concluded.

Study points to new genetic model for disease

Biedel syndrome, a classically Mendelian genetic disease is triallelic.

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