Genetics of PFIC: Current Status and Implications
By Laura Bull, Ph.D.
Associate Professor, Department of Medicine
University of California San Francisco Liver Center Laboratory
San Francisco General Hospital
My primary expertise is in human genetics. I have a research laboratory in the UCSF Liver Center. For the past decade, most
of my work has focused on use of genetic and related approaches to understand the causes of cholestasis, including PFIC.
In this article, I will try to provide an overview of our current understanding of the genetics of PFIC, based upon our
work and that of colleagues in the field. I will also indicate some of what still remains unknown, and finally, discuss some
of the ways in which knowledge of the underlying genetic causes of PFIC can help in the quest to better understand PFIC and
PFIC can be divided into 2 broad categories: ‘Low-gGT PFIC,’ in which serum activity of gamma-glutamyltranspeptidase
is usually low or normal, and ‘high-gGT PFIC,’ in which the activity is above normal. In my laboratory,
we have focused our studies to date on the low-gGT form of PFIC, and especially on FIC1 disease (see below), so that is my
area of greatest expertise.
Some patients with low-gGT PFIC carry mutations in FIC1 (also called ATP8B1), while others carry mutations in BSEP (also
called ABCB11). In other patients, we have been so far unable to detect any mutations in either of these genes. For some
such patients, genetic studies indicate that their disease must be due to mutation in a gene other than FIC1 or BSEP, although
we don’t yet know which gene; it thus seems clear that there is at least one (and maybe more) ‘low-gGT
PFIC gene’ that has not yet been identified.
For some patients in whom no mutations in FIC1 or BSEP are detected, too little genetic information is available, so we
can’t say for sure whether they may have mutation(s) in one of these 2 genes that are just hard to detect, or whether
they may have mutation(s) in the as-yet-unidentified gene(s). Some types of mutation are easier to detect than others, and
in fact, some proportion of possible mutations would not be detectable at all using the techniques that are currently standard
for such studies; detection of such mutations would require much more labor-intensive and expensive studies.
Some patients with high-gGT PFIC have mutations in MDR3 (also called ABCB4), while in other such patients, the genetic
cause of disease is unknown; there may well be at least one more ‘high-gGT PFIC gene’ to be identified.
Some reasons why genetic studies are useful
a. Clues to the primary biological problems resulting in disease
One of the great things about using genetics to identify causes of hereditary disease is that genetics ‘works,’
whether or not we already have an accurate understanding of the biological cause of a disease; therefore, genetic studies
can be particularly valuable in identifying the etiology of disorders that have been difficult to figure out using other approaches,
and in which the cause of the disease might be a surprise to us, given our incomplete understanding of the biology of cholestasis.
While identification of the genetic etiology of a disease provides us with important new information about the primary cause
of a disease, much subsequent work is usually needed to translate that new
information into improved ability to predict the course of disease, and identify the best treatments for patients.
b. Distinguishing subtypes of disease
Another benefit of such genetic studies is that they help us to distinguish different forms, or subtypes, of a disease
from each other. This idea is illustrated in the figure. The top picture shows the situation before genetic studies of PFIC
were begun- only 2 basic types of PFIC could be defined. In the bottom picture, the current situation is illustrated- although
there is still more to be learned, we can now begin to divide the 2 general types of PFIC into subtypes of disease, based
on genetic etiology. (We don’t yet know the precise proportion of PFIC patients with each form of disease; this
figure is meant to illustrate a general concept, but is not to scale.)
BSEP versus FIC1 disease
You may wonder why it is helpful to distinguish subtypes of PFIC. I will try to show why such information is useful using
the example of BSEP disease versus FIC1 disease. Mutations in both BSEP and FIC1 can result in low-gGT PFIC, as noted above.
BSEP (the bile salt export protein) is expressed only in the liver, and is involved in transport of bile acids out of the
liver. The identification of mutations in BSEP in some patients with PFIC made sense, given our understanding of the biology
of cholestasis; it was logical that defects in transport of bile acids out of the liver could cause cholestasis. Given that
the functional defect in BSEP disease is limited to the liver, one might expect that the symptoms and features of BSEP disease
stem ultimately from problems in the liver, and should be very treatable by, for example, liver transplantation.
In contrast, while FIC1 is expressed in the liver, it is also expressed in many other places in the body, including, for
example, the intestine and pancreas. The exact role FIC1 plays is still under study, although it appears most likely to be
involved in transferring certain types of lipid (fat) from one side of cellular membranes to the other; progress is being
made in understanding how such a defect might result in cholestasis. It was certainly initially a surprise that loss of function
of a widely expressed protein that did not appear to be a bile acid transporter could be responsible for a form of PFIC.
The evidence arguing that FIC1 is not a bile acid transporter also raises the possibility that some FIC1 patients, at least
early in their course of disease, may retain more ability to export bile acids from their livers than do patients with severe
BSEP disease. Depending on how important the presence of FIC1 is in the different parts of the body where it is expressed,
we might expect that at least some patients with FIC1 disease would have primary problems with other organs, in addition to
problems stemming directly from their liver disease. Rather than being a single-organ disease, FIC1 disease may better fit
into the category of ‘syndromes,’ in which multiple organ systems are directly impacted by the loss function
of a protein. Treatments for patients with FIC1 disease might have different outcomes than do those same treatments used
in patients with BSEP disease.
In fact, some small studies in the scientific literature appear consistent with the general idea that BSEP disease is
a liver-specific disease, while patients with FIC1 disease can sometimes have problems with other organ systems that are not
secondary to their liver problems. For example, while liver transplantation cures the original liver disease in both BSEP
and FIC1 patients, other problems may continue or develop in FIC1 patients; for example, post-transplant diarrhea appears
to be more of a problem in FIC1, than in BSEP, patients. FIC1 may well play an important role in normal intestinal function.
A study we are currently completing
We are currently completing a large study of PFIC due to FIC1 and BSEP mutation. The unique features of our study of PFIC
are the relatively large number of patients (145) clinically diagnosed with PFIC; and the verified genetic diagnosis of either
FIC1 disease (61 patients) or BSEP disease (84 patients). Most of these patients come from the U.S., Europe, and the Middle
East. In addition to performing genetic studies of these patients, we have collected clinical, biochemical, and treatment-outcome
data. We are currently analyzing these data to identify commonalities and differences between BSEP and FIC1 disease. Through
studying such a large group of patients, we should be able to discern general patterns of disease that aren’t clear
from observing single patients or small sets of patients, due to the variation between individual patients.
We hope that the results of this study will help improve diagnosis of subtypes of PFIC, enable better prediction of what
families can expect their children with PFIC to experience, and improve the ability to identify those patients most likely
to benefit from particular treatments. As this is a retrospective, exploratory study, including patients from many different
places, with correspondingly different healthcare systems, many of the results will be preliminary, and require testing in
additional studies; we hope that results of this current study will, for example, prove useful in planning details of the
PFIC studies to be carried out by the Cholestatic Liver Disease Consortium (http://rarediseasesnetwork.epi.usf.edu/clic/index.htm).
A final note:
I should explain that when I say ‘we’ are doing this study, I mean a large group of researchers involved
in assembly and analysis of the data, including our team here in San Francisco, research teams in London, the U.K. (that group
includes Richard Thompson and Alex Knisely), and Warsaw, Poland (including Joanna Pawlowska and Irena Jankowska), as well
as other physician-researchers in the U.S. and elsewhere. Of course, we are also very appreciative of all of the people who
chose to contribute to the study- both families affected by PFIC who agreed to participate in the study, and their physicians
and other medical personnel who took time from their very busy days to assemble the data from their participating patients
and provide it to us. Without the help of so many people, such a study would be impossible.