LMBBS Laurence Moon Bardet Biedl Society

New research information for families and professionals

Inheritance

Children get LMBBS in the same way as they get blue or brown eyes, their father’s nose or their mother’s ears. The instructions for all of these things come in their genes- copies of instructions from their parents and their parents’ parents. There are some genes that are responsible for causing diseases, such as LMBBS.

Inheritance

LMBBS is a recessively inherited syndrome which occurs in about 1 in 100,000 people born in Northern Europe and America. That means that there will be roughly about 600 people in the UK with LMBBS. Recessive inheritance means that a child has inherited two copies of a faulty gene, one from their mother and one from their father.

In most cases of LMBBS, both parents carry a normal gene (N), and a faulty, recessive gene (n). Although the parents have one copy of the faulty gene and are called carriers of the disease, they are unaffected by the presence of the faulty gene. We each carry two copies of every gene. For a recessive disease to occur, a child has to inherit two faulty copies of the gene; one from each parent.

Some types of LMBBS need mutations (the technical term for a faulty gene) in two separate genes.  This means that in one of the LMBBS genes a patient has two faulty copies, and in another LMBBS gene he/she has one faulty copy and one normal copy. This is called triallelic inheritance (three alleles/mutations).    

Parents who already have an affected child have a much higher chance of having further affected children and should have counselling on this. The child from each pregnancy has a 1 in 4 chance of being affected. If a new born child is not affected then there is a 2 in 3 chance that he/she will be a carrier of the gene for LMBBS.

LMBBS is rare. Many people carry mutations in an LMBBS gene without realizing it; the “carrier rate” is estimated to be approximately 1 in 160. Because genes are passed through families, the risk of having affected children is increased if a carrier marries within their family.

What is a gene?

Every cell in our bodies has genes. Genes carry instructions which influence how our cells and our bodies work.

A gene is a stretch of DNA located on our chromosomes. Chromosomes are found packaged into the nucleus of every single cell in our bodies.  A particular stretch of DNA (gene) gives the cells instructions to make a particular type of protein. For example the gene for BBS1 (which is located on chromosome 11 of 23) encodes the information for the cell to make the BBS1 protein. Proteins are the chemicals that make things happen in our bodies.

A gene is the instruction needed for the cell to make a particular type of protein.

We inherit our genes from our parents, and we each have two copies of every gene, one coming from our mother and one from our father. The nucleus of each cell contains 23 pairs of chromosomes (23 inherited from our mother and 23 from our father).

These chromosomes are extremely long stands of DNA which are tightly packaged together. The DNA that the chromosomes are made from can be read by the cell to give the cell instructions to make all of the components (the proteins) it needs. Simply put, a gene codes for a protein.

Just like a house is made up of many individual bricks, humans are made up of millions of different types of cells. Although we have many different types of cells (i.e. skin cells, bone cells, blood cells), the cells themselves are made up of even smaller building blocks called proteins.
 
    

Sometimes mistakes occur in the DNA encoding a gene, these are called gene mutations. When these mistakes happen, the corresponding protein is often not formed correctly, and in some cases is not made at all.  Depending on the severity of the mutation this can result in disease. 

BBS genes and Proteins

So far scientists have identified 12 LMBBS genes. Scientist know that there are still more genes to find as not all patients have an identified fault (mutation) in those 12 LMBBS genes. This means that these patients must have mutations in other genes. 

The table below shows all the different genes identified to date. The chromosome column shows which chromosome they are located on (eg BBS1 is on Chromosome 11) and where they are on that chromosome. The % contribution column shows how likely it is for someone with LMBBS to have a mutation in this gene.
 

The protein that these genes give instructions for is listed in the protein column. Scientists don’t yet know what the functions of most of these proteins are. However in the past few years people in Professor Phil Beale’s lab and other labs around the world have done a lot of work into establishing what these proteins do. Scientists are now certain that BBS proteins are involved in ciliary function. Currently more work is being carried out to fully determine the role these BBS proteins play in cells.   

Cilia

Why should I be interested in Cilia?
Cilia are structures found on almost every cell in our bodies. Scientists currently think that the symptoms in LMBBS patients are caused by cilia not working properly.

What are Cilia?

Cilia (singular – cilium) are thin, tail-like projections extending approximately 0.1 mm outwards from the cells. There are two types of cilia, motile cilia (moving cilia) and non-motile cilia. Motile cilia constantly beat in a single direction, whilst non-motile cilia typically sense the cells’ environment. Non-motile cilia are often referred to as ‘primary’ cilia.

What do they do:
 

As the name suggests, motile cilia are involved in movement. As they constantly beat in a single direction, they can help a cell move around. They also do the job of moving other ‘things’ (fluid) along. As these types of cilia are usually present on a cell’s surface in large numbers, they beat in coordinated waves. An example of motile cilia can be found in humans in the lining of the windpipe, where they sweep mucus and dirt out of the lungs.

Normally a cell only has one non-motile cilium. There are some cells in the body that have a specialized primary cilium which have a very important job to do.

For example in the human eye, there is a primary cilium that connects the outer segment of the rod photoreceptor cell to its cell body. When you get problems with these cilia that you can get retinitis pigmentosa (RP).
Though the primary cilium has historically been ignored by scientists, research has now shown that this structure is involved in many important cell processes such as sensing its environment, cell growth and also cell development. These recent findings have led scientists to re-evaluate the importance of this structure. This is what has made LMBBS a well known cilia disease.
What are cilia of and how do they work?
A cilium is put together from smaller building blocks. The main component of these building blocks is a protein called “tubulin”, however other proteins are also involved. Cells need to maintain their cilia and supply them with materials. Proteins and other cargo are moved up and down the cilium by “molecular motors”. This process is called intraflagellar transport and it is vital for the maintenance and function of the cilium.

This is a picture of a cilium showing where the BBS proteins are. Most of them sit at the bottom of the cilia, at a place called the basal body. The basal body is like the anchor of the cilium, joining it to the cell. Many of the BBS proteins are involved in intraflagellar transport and so can be found along the cilium as well.

What happens when things go wrong? Cilium-related diseases
Sometimes cilia don’t function properly. This is usually because of a problem with the intraflagellar transport. This causes problems in cells, especially the ones that rely heavily on specialized cilia, such as the photoreceptor in the eye and particular cells in the kidney.

Diseases where there are problems with cilia are called ciliopathies. LMBBS has been classified as one such ciliopathy, others include Alström syndrome, Meckel-Gruber syndrome and nephronophthisis. Scientists are still trying to find out exactly how the problems at the cilia lead to the symptoms of the disease.