Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis.
Recent work has demonstrated enhanced X monosomy in women with primary biliary cirrhosis (PBC) as well as two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease. To further our understanding of these events, we have investigated the mechanisms of X chromosome loss and X chromosome inactivation (XCI) in 166 women with PBC and 226 rigorously age-matched healthy and liver disease controls. X chromosome analysis and determination of loss pattern was performed by quantitative fluorescent polymerase chain reaction (QF-PCR) with 4 X-linked short tandem repeats. Further definition of the XCI was based on analysis of methylation-sensitive restriction sites. Importantly, in PBC the X chromosome loss occurs not only more frequently but also in a preferential fashion. This observation supports our thesis that the enhanced X monosomy involves only one parentally derived chromosome and is not secondary to a constitutive non random pattern of XCI. In fact, in the presence of monosomy, the lost X chromosome is necessarily the inactive homologue.


CONCLUSIONS
The finding that the X chromosome loss is preferential suggests the critical involvement of X chromosome gene products in the female predisposition to PBC and also emphasizes the need to determine the parental origin of the maintained chromosome to investigate the role of imprinting.
Medical Genetics Unit, San Paolo Hospital School of Medicine, University of Milan, Milan, Italy.
Monica
M
Miozzo
Carlo
C
Selmi
Barbara
B
Gentilin
Francesca R
FR
Grati
Silvia
S
Sirchia
Sabine
S
Oertelt
Massimo
M
Zuin
M Eric
ME
Gershwin
Mauro
M
Podda
Pietro
P
Invernizzi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged