By David N. Leff

Georges Bardet of France and Artur Biedl of Austria are not household names ¿ except in households with Bardet-Biedl syndrome running in the family.

This exceedingly rare inherited malady, guesstimates molecular geneticist Nicholas Katsanis at Baylor College of Medicine in Houston, ¿has an incidence in the North American and European populations of about 1 in 120,000 persons. For people who happen to live in Newfoundland or Kuwait, and Saudi Arabia, that number is somewhere between 1 in 12,000 and 1 in 24,000. In Kuwait and Saudi Arabia, first-cousin and consanguineous matings are fairly common, and lead to elevating diseases such as Bardet-Biedl syndrome (BBS).

¿We believe that the syndrome starts out while developing in the womb,¿ he observed, ¿and then gets worse as postnatal life gets going. But when we first detect BBS in the clinic, its signs and symptoms vary. They show up anywhere from newborns on; BBS typically gets diagnosed around age 7.

¿Its first visible feature, polydactyly ¿ extra fingers and toes ¿ is detected immediately. But it¿s not a major concern, because it can be treated surgically. The first big problem with the disease,¿ Katsanis continued, ¿is night blindness, which leads to total blindness. It typically gets detected by age 7. Most kids are totally blind by 14 or 15.

¿The other early problem is that young patients become grossly obese around the trunk, not the limbs, which brings its own health problems. The main cause of death,¿ Katsanis pointed out, ¿is kidney failure. Those who get it, unless treated with dialysis or organ transplants, just die.¿

Katsanis is the lead author of a paper in today¿s Science, dated Sept. 21. 2001. Its title: ¿Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.¿

¿The overall finding,¿ he told BioWorld Today, ¿is that it takes more than one gene to get a genetic disease. Traditionally,¿ Katsanis explained, ¿we tend to divide genetic disorders into two categories: Mendelian diseases and complex traits. Typical Mendelian diseases are neurofibromatosis, cystic fibrosis, sickle cell anemia ¿ the sort of malady familiar to most people.¿

BBS Models More Important Complex Diseases

¿Research on these recessive, single-gene ailments,¿ he observed, ¿has gone on very rapidly the last 20 years or so. And our understanding of how mutations in particular genes cause this or that particular disease has progressed. We know much less about multigenic, complex diseases such as asthma, diabetes mellitus, hypertension, as well as behavioral disorders ¿ schizophrenia and polar depression. These are more complex for two reasons. First of all, because they have a synergistic effect involving more than one gene, and mutations in more than one gene, which cause the disease ¿ along with an environmental component.

¿Until now Bardet-Biedl syndrome looked and behaved like a Mendelian disease,¿ Katsanis observed, ¿when we saw it in afflicted families. However, solving the genetic basis of this disorder is now proving to place BBS somewhere between Mendelian and complex traits. To cause the disease, patients must have two mutations in one gene and one mutation in a second gene.

¿The importance of this finding,¿ Katsanis went on, ¿is that it¿s a model-building exercise. So we can use this disease now to study how genes cooperate with each other, or how the dysfunction of more than one gene at the same time is actually causing the disorder. That, hopefully, will give us a better handle on building models for understanding how the interaction of multiple genes is giving rise to the disease, which is very pertinent for serious health issues in the population.

¿The main novel feature in this finding,¿ he continued, ¿is that the traditional requirement in a disease that is Mendelian recessive calls for one mutant copy from your dad, who is unaffected, and one mutant copy from mom, who is also unaffected. These two carrier genes get passed on to the same child, and the child gets Bardet-Biedl syndrome. That¿s the standard recessive Mendelian pattern. It very much follows the rules set up by Gregor Mendel a century and a half ago, with his garden peas.

¿What is happening here is that we have a disease presenting itself in that way, yet requiring two genes and three parental alleles. That is really the key point. Now we have had some idea that in many cases we do need more than one gene to cause disease. And there are some sketchy examples of that in the scientific literature. However, this Science paper provides the first strong piece of evidence of what is actually going on at the genetic level, at the level of DNA, to get this kind of disease.¿

Katsanis and his co-authors in Britain and Canada pooled their collections of DNA in 163 BBS families, and carried out genetic linkage analysis on all affected and unaffected members. Their genomic sweep, and that of others, pinpointed three mutant genes, BBS 2, 4 and 6, on as many chromosomal loci, and mapped another three ¿ BBS 1, 3 and 5, as yet unidentified.

Why Only One Sibling Got BBS

¿We wound up with four pedigrees that had mutations at both the BBS6 and BBS2 genes,¿ he recounted. ¿Three pedigrees had two mutations on BBS2 and one on BBS6. And one pedigree had three mutations on BBS6 and one on BBS2. In one pedigree both the affected kid and his unaffected brother had two mutations, but only the affected child had an extra mutation on BBS6. So that led us to hypothesize ¿ and this is really the cornerstone of our Science manuscript ¿ that in some patients, two mutations are not sufficient to cause disease. Because if they were, both these kids would have it. The difference between them was that the affected patient had a third mutation on BBS6. That led us to the very important statement that three mutations in Bardet-Biedl syndrome are both necessary and sufficient to cause the disease.

¿Our next step, now ongoing, is to ask how those two or three or more proteins those genes encode interact, at the cellular level. Then we can think about identifying such pathways in other diseases with complex traits. For example, attacking diabetes from a pharmaceutical point of view.¿

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