SRDA5
GENE
AND ITS LOCUS
The genes that code for 5-alpha
reductase, whose catalytic function with DHT triggers hair loss, are SRDA51 and
SRDA52. The two genes produce two
types of functionally similar enzymes (isoenzymes) called type 1and type 2
alpha-reductase, as discussed in the introduction and protein analysis. The SRDA51 gene and SRDA52 gene, both located on chromosome 5,
have their loci designated as 5p15 and are determined by using cDNA and in situ
hybridization.1
CHROMOSOME
5
In addition to SRDA5 the
"baldness" gene, chromosome 5 also contains genes linked to dwarfism,
immunodeficiency, schizophrenia, colorectal cancer, basal cell carcinoma,
deafness, acute myelogenous leukemia, susceptibility to obesity, and atrial
defect of the heart.2 GDB.org provides one of the more
complete and up-to-date lists of genes found on chromsome 5.3
Of interest is this chromosome harboring two genes that contribute to
asthma (which affects 5% of the US population), whose gene discoveries were
made right here in the Bay Area at the Lawrence Berkeley National Laboratory in
Berkeley in 1999.4
The Human Genome Project estimates that
chromosome 5 contains 194 million bases, which represents roughly 6% of the
human genome.5 Sayer Lab in Japan has determined the existence of 198 million bases,
4,044 of which they have sequenced.6
GenomeAtlas, a Danish research lab, has calculated 203,085,532 base
pairs, 49% of which are adenine and thymine.7
NCBI has listed a total of 1196 genes on chromosome 5, which reflects a
gene density of about 6.16 gene per million base pairs, keeping in mind that
gene density varies with regions of the chromosome.8
INHERITANCE
The genetics of pattern baldness is still
not fully understood. It was first
defined 80 years ago as an autosomal dominant trait with various degrees of
penetrance (expressivity), although recent studies have suggested a polygentic
inheritance pattern.9 Associated with baldness are elevated
DHT levels, greater number of DHT receptors in the scalp and higher levels of
both serum and free testosterone.
Pattern baldness is also be a classic textbook example of a sex
influenced trait sine expression depends on hormonal differences between
sexes. Testosterone, as discussed
in the introduction, is needed for the full expression of this "disorder." The effect is such that in male, the
allele for baldness behaves as a dominant trait, expressing itself when
heterozygous. But in female, the
allele behaves as a recessive, which must be homozygous in order to express the
trait.10 On the molecular level, however, the
genetics of pattern baldness is more complex and requires further study.
An area of uncertainty is the direct
connection between the reductase genes and pattern baldness. Thigpen et. all
(1993), by detecting the presence of the reductase isoenzymes in fetal, newborn, and adult tissues, concluded
that SRDA51 is probably responsible for masculination at the onset of puberty,
while SRDA52 affects the initiation of pattern baldness.11
However, when Ellis et. all (1998) surveyd a population of 8228 health
families with 3,000 individuals and compared 58 young balding men (aged 18 to
30 years) and 114 older nonbalding men (aged 50 to 70 years), no significant
differences were found between alleles and genotype frequencies for RFLPs
(restriction fragment length polymorphism) related to either SRDA51 or SRDA52.12
This seems to suggest that the genes are not associated with pattern
baldness. While that may be true,
it is possible that other genes must be involved in conjunction with SRDA in
order for baldness to manifest.
PROBABILITY
OF INHERITANCE
Calculating the probability of a newborn
developing pattern baldness later in life is difficult because there are no
extensive research studies to define frequency of pattern baldness. The newborn's race and ethnicity are
significant factors in such a calculation. Some dermatologist (Dawber), for
examples, suggest that hair loss can begin in Caucasian male as early as teenage years and frequency in elderly
male Caucasians can reach almost 100%.13
In addition, the polygenic nature of pattern baldness means that the
newborn's future lifestyle and environment will play a significant role in the
development of pattern baldness.
The conversion of testosterone to DHT is
a normal function of 5-alpha reductase.
Pattern baldness is not a result of mutated SRDA5 genes since mutation
would lead to a decrease in DHT level.
Instead, mutation in the SRDA5 genes will lead to disorders related to problems
with prostate differentiation or secondary sexual organ development among other
possibilities. In fact, by using
different restriction enzymes, Rodriguez et. all (2002) have found extensive
cytosine methylation pattern in patients deficient in type 2 isoenzyme,
suggesting an increase rate of
mutation in SRDA52 by methylation.14
REFERENCE
1.
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=184753. Accessed 3/15/03
2.
http://www.the-scientist.com/yr2000/jul/emmett_p18_000724.html. Accessed 3/15/03.
3.
http://gdbwww.gdb.org/gdbreports/GeneByChromosome.5.alpha.html. Accessed
3/15/03.
4.
http://www.the-scientist.com/yr2000/jul/emmett_p18_000724.html. Accessed
3/15/03.
5.
http://www.ornl.gov/TechResources/Human_Genome/posters/chromosome/chromo05.html.
Accessed 3/15/03.
6.
http://sayer.lab.nig.ac.jp/~silver/gorilla.html. Accessed 3/15/03.
7.
http://www.cbs.dtu.dk/services/GenomeAtlas/Eukaryotes/index_Size.html. Accessed
3/15/03.
8.
http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?org=hum&chr=5&MAPS=genec,ugHs,genes[6065711.00:7043856.33]-r&query=uid(6402)&QSTR=SRD5A1,
Accessed 3/15/03.
9.
http://www.hairtransplantation.com/advances/male.html. Accessed 3/15/03.
10.
http://www.emporia.edu/biosci/genetics/note5.htm. Accessed 3/15/03.
11.
Thigpen, A. E.; Silver, R. I.; Guileyardo, J. M.; Casey, M. L.; McConnell, J.
D.; Russell, D. W. : Tissue
distribution and ontogeny of steroid 5-alpha-reductase isozyme expression. J.
Clin. Invest. 92:
903-910, 1993.
12.
Ellis, J. A.; Stebbing, M.; Harrap, S. B. : Genetic analysis of male pattern baldness and the
5-alpha-reductase genes. J. Invest. Derm. 110: 849-853, 1998.
13.
Rodriguez-Dorantes M, Lizano-Soberon M, Camacho-Arroyo I, Calzada-Leon R,
Morimoto S, Tellez-Ascencio N, Cerbon MA. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11948017&dopt=Abstract.
Accessed 3/15/03.
14.
http://www.keratin.com/ac/baldnesspatterns/baldnessepidemiology/001malebaldnessiscommon.shtml.
Accessed 3/15/03.