Using mouse models to investigate sex-linked genetic effects on brain, behaviour and vulnerability to neuropsychiatric disorders

Abstract

Many brain and behavioural phenotypes in humans exhibit some degree of sexual dimorphism. Moreover, there are large and replicable differences in the vulnerability of the two sexes to a wide range of common brain disorders. Ultimately, sex differences in healthy individuals, or in pathological states, must arise as a consequence of the differential complement of sex-linked genes in males and females. These genes may act indirectly (for example through influencing gonadal hormone secretion), or directly, to influence brain development and function. In this review, I discuss how genetically tractable mouse models may be employed to inform our knowledge of the molecular basis of sexual differentiation of the mammalian brain, and how such models may therefore represent a useful tool through which to identify risk factors predisposing to sex-biased neuropsychiatric disorders.

46,XY Disorder of Sex Development in a Sudanese Patient Caused by a Novel Mutation in the <b><i>HSD17B3</i></b> Gene

“…Eventually, sex differences must arise as a consequence of the differential complement of sex-linked genes in males and females. These genes may act indirectly -through influencing gonadal hormone secretion -or directly, to influence brain development and function [Davies, 2013]. The fact that the patient still wishes to change her gender role from female to male demonstrates that genetic, hormonal and cultural influences must have had overwhelming influences over genital appearance alone in developing the individual wishes for a gender role change in this patient.…”

Attention deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies

“…The X-monosomic 39,XO mouse model [26] appears to recapitulate, to some extent, the parietal cortex and striatal structural abnormalities reported in TS [25]. However, it should be noted that the extrapolation of any findings from this work to humans is limited by the fact that there are far fewer X-escapees in the mouse than in human, and the physiological consequences of X-monosomy in the mouse are likely to be different, and generally less severe, than in human [27]. …”

“…A comparison of whole brain gene expression in 40,XX and 39,XO mice revealed only a very small number of significantly differentially expressed genes [104] including the X-inactivation escapees Eif2s3x , Utx and Ddx3x , none of which have previously been implicated in ADHD. To reiterate, the relevance of the 39,XO mouse model for understanding the molecular neuropathology of TS is debatable given the lack of X-escapees in mice relative to humans [27]. Gene expression studies in heterozygous NF1 knockout mice have focussed on the hippocampus (largely because of its key role in learning, memory and spatial processes).…”

Assessment of Quality of Life, Anxiety and Depression in Children with Turner Syndrome: A Case-Control Study

“…The similar clinical picture is found with isochromosome (isoXq), ring chromosome X and deletion of the short or long arm of X chromosome (Donaldson et al, 2006). Monosomy (45,X) accounts for more than 50% of the karyotypes, while the remaining karyotypes show a mosaic pattern (Davies, 2013;Donaldson et al, 2006). Turner syndrome occurs in approximately 1 in 2,000 live female births (Donaldson et al, 2006;Saad et al, 2014).…”

“…Turner syndrome is a genetic disorder that affects only females and is caused by the loss of the whole or a part of the X-chromosome (Davies, 2013). It is one of the most common chromosomal aberrations.…”