The Contribution Made by X-Linked Imprinted Genes to Brain Development in Humans

David Skuse
Behavioural Sciences Unit; Institute of Child Health

Many neurodevelopmental. disorders, such as autism, are sexually dimorphic in their clinical course and phenotype (7). Social communication impairment is substantially more common among males than females (4,5). Male vulnerability has conventionally been attributed to neuroendocrine mechanisms (1). An alternative explanation will be proposed. Recent evidence for imprinting of the X-chromosome comes from observations of Turner syndrome, a sporadic disorder of human females in which all or part of one X chromosome is deleted (2). We have postulated the existence of an imprinted locus that is expressed only from the paternally inherited X (6) and which is associated with superior social communication skills. Such a locus would not be expressed in males, whose single X is always maternal in origin.

Evidence that X-linked loci influence specific areas of brain development will be presented (3). We found X-monosomy as such is consistently associated with grey-matter reductions in cognitive brain systems that are mainly associated with social cognition. Turner females lacking a paternal X-chromosome (45,Xm) have reduced grey matter density in an area contiguous with one such system, suggesting imprinting of the X may have evolved to influence cortical development in areas already controlled by non-imprinted X-linked loci that are important for social communication. Turner females lacking a maternal X-chromosome (45,Xp) have reduced grey matter in a medial frontal region that is activated by tasks that demand the retrieval of motor memories. Our findings are consistent with the hypothesis that both paternally and maternally expressed X-linked imprinted genes contribute to sexually dimorphic traits and abilities, such as superior social communication abilities in females and superior motor skills in males.


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