X chromosome imprinting in fragile�syndrome

Abstract

Laird et al. (1987) hypothesized that there are at least four cis-acting alleles or 'chromosome states' at Xq27 that increasingly delay replication at this chromosomal area resulting in its increasing fragility in vitro. When on the inactive X chromosome, the proposed third ('mutated') allele can permanently block reactivation of its cis Xq27 area as the chromosome passes through female meiosis. Males and some females who inherit such an 'imprinted' fragile X chromosome (the fourth proposed allele) will be clinically affected due to impaired transcription of genes in the 'imprinted' Xq27 area. To test this hypothesis, late replication reverse banding patterns at Xq27 were evaluated in cultured lymphoblastoid cell lines from 25 subjects. Our data suggest that DNA replication of the presumed 'imprinted' Xq27 region in affected fragile X patients is indeed later relative to Xq27 on the active X chromosome in other subjects. These results support in part Laird's hypothesis of chromosomal imprinting in fragile X syndrome.

Estimating the stability of the proposed imprinted state of the fragile-X mutation when transmitted by females

“…Reiss et al (1989) have reported clinical differences between female fragile-X carriers, classified cytogenetically as either imprinted or nonimprinted. Yu et al (1990) have presented preliminary cytogenetic data in accord with one aspect of these suggestions: DNA in the Xq27.3 band in cells from affected fragile-X males is apparently later replicating than the corresponding region in cells from either normal males or nonpenetrant fragile-X carrier males. Finally, the predicted pattern of methylation associated with the imprinted state of the fragile-X allele has been detected in a CpG island near the fragile-X site Bell et al 1991;Heitz et al 1991;Verkerk et al 1991); this CpG island is close to the apparent site of the fragile-X mutation Yu et al 1991) and the 5' end of a candidate gene (Verkerk et al 1991).…”

Inability to induce fragile sites at CTG repeats in congenital myotonic dystrophy

“…FRAllB, also having similar molecular composition to the other folate-sensitive fragile sites, is associated with a chromosome deletion, Jacobsen syndrome [Jones et al, 19951. The above five folate-sensitive fragile sites are associated with methylation at a nearby CpG island when the number of trinucleotide repeats exceeds 200 [Bell et al, 1991;Knight et al, 19931, which at least for fragile X syndrome results in the absence of mRNA [Pieretti et al, 19911. Gene inactivation has been associated with late or delayed DNA replication, which has been demonstrated in fragile X syndrome both cytogenetically [Yu et al, 1990;Webb, 19921 as well as molecularly [Hansen et al, 19931. However, methylation has not been found associated with the DM gene [Shaw et al, 19931, and imprinting is not involved in allelic expression [Jansen et al, 19931. Our results suggest that CTG repeats behave differently from other large expansions.…”

Polymorphisms in the mitochondrially encoded ATP synthase 8 gene are associated with susceptibility to bullous pemphigoid in the German population

“…One of the subunits of complex V, ATP synthase protein 8 (or A6L), is encoded by the mitochondrially encoded ATP synthase 8 gene (MT-ATP8) (2). Our group and others have experimentally demonstrated that a mutation in MT-ATP8 increases disease severity via increased ROS levels in several autoimmune disease models, including collagen-induced arthritis and lupus (7). Interestingly, a mutation in MT-ATP8 was found in a patient with multiple sclerosis (s2).…”