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Introduction
Most of the advances in genetics we hear about on the news involve
one or two gene mutations that code for a specific disease and follow
a Mendelian genetic inheritance pattern. One such gene is the recent
"hairless" gene identified in humans by Angela Christiano
and friends at Columbia University (Ahmad 1998). The "hairless"
gene causes the permanent hair loss disease "generalized atrichia".
The initial announcement of finding this gene caused considerable
excitement in the news media in February 1998. Most of the news
reports were rather confused in their explanation of the gene discovery.
In the Mendelian genetics of generalized atrichia a recessive
gene is passed from parent to child. A recessive gene is one that
only shows up as a clinical disease when two mutated genes, one
from each parent, are brought together in a child. In generalized
atrichia the parents must both be affected or both be carriers of
the gene mutation (or one of each type). This makes it quite difficult
for the disease to clinically develop in a person and consequently
generalized atrichia is a very rare disease and usually only observed
in families where there has been a degree of inbreeding.
The
"hairless" gene
There is a mouse strain called HRS that has a single gene mutation
on mouse chromosome 14. There are several different substrains of
this mouse that have different types of mutation in the same gene.
The two most important substrains for us are called “hairless”
and “Rhino”.
Rhino mice have been with us for a long time. It seems that this
genetic disease is a spontaneous mutation that can occasionally
be observed in wild mice. The very first report on a Rhino mouse
was published in 1856. Several wild mice were captured near Maidenhead
in England with no hair and very wrinkly skin. Apparently these
mice were common in the area as local people had nicknamed them
Rhinoceros mice. Similar specimens to these mice were subsequently
found preserved since 1820 in the museum of the Royal College of
Surgeons.
All Rhino mice are born bald - they have no hair. During the first
few days of life they grow their first coat of hair and this happens
in Rhino mice too. But unlike normal haired mice, Rhino mice never
grow another coat of hair again. As the hair follicles cycles through
growth and into a resting stage they involute and atrophy in Rhino
mice. The hair fiber falls out and is not replaced by any new hair
growth. The Rhino mice become bald and progressively develop wrinkly
skin.
As often occurs with other genetic diseases there can be "remutations".
This means that if the genetic mutation can spontaneously develop
in one mouse once it can spontaneously happen in another mouse.
Subsequent to the discovery of Rhino mice other mice have been found
with hair loss and wrinkled skin to various degrees. One such mouse
was bred to produce the mouse strain with the “hairless”
gene mutation. These mice have a defect in the same gene as Rhino
mice and they are bald but unlike Rhino mice they do not have wrinkled
skin. The same gene is mutated in different ways in the “hairless”
mouse strain and the Rhino mouse strain. The same mutated gene can
also be found in a strain of “hairless” rats.
Mice from one of the “hairless” mouse substrains were
set up in what is called a backcross breeding study. In these studies
a mouse with the “hairless” gene was bred with a normal
mouse. The offspring of this cross were then bred with more normal
mice. The second generation offspring were examined to find which
ones had hair loss and which ones were normal. The DNA of offspring
were screened by a common procedure called Polymerase Chain Reaction.
This method allowed the identification of the source of genes on
each mouse chromosome. The researchers could see that those mice
with hair loss always had one particular area of mouse chromosome
14 that was derived from the original “hairless” mouse
grandparent. All other areas of this chromosome and other chromosomes
could come from either “hairless” or normal grandparent
and so were plainly not the location of the “hairless”
gene. Once the location of the mouse “hairless” gene has
been found that part of the chromosome was biochemically cut out
and the DNA sequenced to work out the genetic code for the gene.
In much the same way the investigators at Columbia University
took DNA samples from members of a family who had generalized atrichia.
The DNA was screened and regions of the human genome identified
that consistently showed up in all those who were affected. With
this knowledge and a map of the family tree, the investigators could
identify those who were carriers for the gene and how the gene was
passed through offspring in the family.
To make sure that they had the right location and the right gene
the investigators used a different process to compare the gene in
humans and the known mouse “hairless” gene. With the genetic
code of the mouse “hairless” gene identified and published
the researchers could use the code sequence and compare it to the
human genome. Where ever the mouse gene code closely matched up
with the human gene code would identify the human gene equivalent.
The human gene equivalent was identified on chromosome 8 (8p12).
What
is generalized atrichia?
Generalized atrichia is the hair loss disease that the “hairless”
gene causes. The “hairless” gene is a recessive gene which
means that both parents of a child with the disease must have the
disease themselves or at least be carriers for the defective gene.
Because of this generalized atrichia is an extremely rare form of
hair loss. So far only about 6 families have ever been identified
that have members with this type of disease. Less than 100 people
worldwide are known to have generalized atrichia. For the most part
these families are inbred with related individuals marrying each
other and having affected children.
In humans generalized atrichia develops much as is seen in mice.
New born babies do have some hair but shortly after birth the hair
growth stops and never grows again. Looking skin biopsies under
the microscope the hair follicles can be seen to be few and far
between. It looks as though many are completely destroyed. The remaining
hair follicles are dilated with a complete absence of hair fiber
production. The skin is otherwise normal. There is never any hair
regrowth, this is a permanent form of alopecia.
Does
the “hairless” gene relate to alopecia universalis?
When details of the “hairless” gene discovery were announced
the news media had a veritable feeding frenzy. However, in their
zeal to present the story they failed to check their facts. Consequently
some very confused reports were made on television and in the news
papers.
The greatest source of confusion was the fact that the authors
of the medical journal article used the title "alopecia universalis
associated with a mutation in the human “hairless” gene".
Alopecia universalis is a form of hair loss that involves inflammation
of the hair follicle and can be reversible. It is a more extensive
form of the disease alopecia
areata of which there is more elsewhere on this web site. What
the authors of this journal article were actually referring to was
a disease in which universal alopecia develops called generalized
atrichia. Generalized atrichia does develop into universal alopecia
but it is NOT alopecia universalis. Many people with alopecia areata
or alopecia universalis have been getting very confused by the news
reports. Generalized atrichia does not involve any inflammation
of the hair follicles. It is a very rare genetically inherited form
of hair loss.
The investigators have received a lot of criticism for the use
of the term alopecia universalis to describe the disease the family
has that was used to obtain DNA samples. Several critical letters
in response to the article are published in medical journals on
this matter. The investigators used the term alopecia universalis
because this was the term used in the original paper describing
this family and because this was the official designation of the
disease on the Online Mendelian Inheritance of Man (OMIM) web server.
OMIM was also incorrect to use this term.
Unfortunately OMIM persist in calling it alopecia universalis
congenital despite initial attempts to get them to alter the statement
and provide a new designated term. They have at least added a sentence
to make it clear that Dr Christiano's paper does not relate to inflammatory
alopecia areata. See OMIM entry #203655.
However, for the rest of the dermatological community the term
alopecia universalis was retracted shortly after publication and
the investigators now use the disease name generalized atrichia.
However, the damage is done and the rumors and confused explanations
persist from what I can see of the personal Email I get on the subject.
What
does the “hairless” gene discovery mean for hair research?
Although the research on the “hairless” gene is important
in our understanding of how hair follicles are made and grow, it
does not have a direct bearing on the inflammatory form of alopecia
areata.
In practice this research will have a limited impact on our understanding
of alopecia in general, including androgenetic alopecia. The gene
sequence in the “hairless” mouse has been known for several
years and the research using the mouse has concluded that it is
an interesting anomaly but that the gene has no real impact on alopecia
research other than for those few people who have the generalized
atrichia form of hair loss.
However, the research does have significant impact on academic
hair biology research. This work is the first to identify a gene
that is directly involved in maintenance of the hair follicle structure.
It shows that mouse models of human disease can be used to identify
important genes in hair biology and disease. These identified mouse
genes can then be compared to the human genome to identify human
gene equivalents. This research technique forms a template for finding
on other genes involved in hair growth and hair disease. Several
mouse models with hair diseases are now being screened in similar
fashion to the above research to identify genes that will then be
looked for in humans. It may be possible to identify genes involved
in such diseases as androgenetic alopecia and alopecia areata in
this way.
The research may not have a direct impact on alopecia treatment
but it does open the door to an effective method of identifying
and characterizing genes that may be involved in a variety of alopecias
where genetic inheritance plays a part. This is an exciting avenue
of opportunity for academic hair research.
The
“hairless” gene references
- Panteleyev AA, Paus R, Christiano AM.
Patterns of hairless (hr) gene expression in mouse hair follicle
morphogenesis and cycling. Am J Pathol. 2000 Oct;157(4):1071-9.
- Aita VM, Ahmad W, Panteleyev AA, Kozlowska
U, Kozlowska A, Gilliam TC, Jablonska S, Christiano AM. A novel
missense mutation (C622G) in the zinc-finger domain of the human
hairless gene associated with congenital atrichia with papular
lesions. Exp Dermatol. 2000 Apr;9(2):157-62.
- Ahmad W, Panteleyev AA, Christiano AM.
The molecular basis of congenital atrichia in humans and mice:
mutations in the hairless gene. J Investig Dermatol Symp Proc.
1999 Dec;4(3):240-3.
- Ahmad W, Panteleyev A, Christiano AM.
Molecular basis of congenital atrichia in humans and mice. Cutis.
1999 Oct;64(4):269-76.
- Panteleyev AA, Botchkareva NV, Sundberg
JP, Christiano AM, Paus R. The role of the hairless (hr) gene
in the regulation of hair follicle catagen transformation. Am
J Pathol. 1999 Jul;155(1):159-71.
- Ahmad W, Zlotogorski A, Panteleyev AA,
Lam H, Ahmad M, ul Haque MF, Abdallah HM, Dragan L, Christiano
AM. Genomic organization of the human hairless gene (HR) and
identification of a mutation underlying congenital atrichia
in an Arab Palestinian family. Genomics. 1999 Mar 1;56(2):141-8.
- Zlotogorski A, Ahmad W, Christiano AM.
Congenital atrichia in five Arab Palestinian families resulting
from a deletion mutation in the human hairless gene. Hum Genet.
1998 Oct;103(4):400-4.
- Ahmad W, Faiyaz ul Haque M, Brancolini
V, Tsou HC, ul Haque S, Lam H, Aita VM, Owen J, deBlaquiere
M, Frank J, Cserhalmi-Friedman PB, Leask A, McGrath JA, Peacocke
M, Ahmad M, Ott J, Christiano AM. Alopecia universalis associated
with a mutation in the human hairless gene. Science. 1998 Jan
30;279(5351):720-4.
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