Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.

The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice. Introduction SOX2 is a member of the sex-determining region of the Y chromosome-related (SRY-related) high-mobility group (HMG) box (SOX) family of transcription factors, encoded by 20 genes in humans and mice, each of which carries a 79-amino acid HMG box DNA-binding domain similar to that of SRY as well as domains implicated in transcriptional regulation (1, 2). Based on HMG box homology, they are grouped into different subfamilies. SOX1, SOX2, and SOX3 belong to the B1 subfamily and are expressed in various phases of embryonic development and cell differentiation, where they play critical roles in embryogenesis (3, 4). All 3 mark neuroepithelial progenitors and stem cells from the earliest stages of development, and there is a strong, but not absolute, tendency for them to be downregulated as cells differentiate.In the mouse, Sox2 RNA is first detected in cells at the morula stage (2.5 dpc) and then in the inner cell mass of the blastocyst (3.5 dpc).

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age ϭ 15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study. (Pediatr Res 67: 357-362, 2010) N umerous studies report that breastfeeding is associated with higher scores on tests of neurodevelopment and cognition in later life (1,2), suggesting that breast milk may impact early brain development, with potentially important biologic, medical, and social implications. These findings are often questioned because other factors associated with mothers' choice to breastfeed (e.g. higher socioeconomic status and level of education, different child-rearing attitudes) might promote cognitive development. In a study using data from a national database, adjustment for maternal intelligence quotient (IQ) eliminated the breastfeeding effect (3). All these studies, however, are potentially flawed by lack of experimental design.More recently, a large cluster randomized trial of breastfeeding promotion using an experimental design demonstrated a large effect of breastfeeding on cognition, adding credence to the evidence for beneficial effects seen in past observational studies (4). Anderson et al. (5) showed in a meta-analysis that, after appropriate adjustments, breastfeeding was associated with an advantage of around three points on tests of cognition in children born at term and around five points in those born preterm, both large effects in population terms. The implication is that, over and above social factors, one or more constituents of breast milk benefit neurodevelopment, particularly so in those born preterm, at a more sensitive stage of brain development.Our current study was prompted by two factors, the now likely causal relationship between breastfeeding and cognition and the previous observation that cognitive scores in preterms are rela...

Early nutrition in animals affects both behavior and brain structure. In humans, randomized trials show that early nutrition affects later cognition, notably in males. We hypothesized that early nutrition also influences brain structure, measurable using magnetic resonance imaging. Prior research suggested that the caudate nucleus may be especially vulnerable to early environment and that its size relates to IQ. To test the hypothesis that the caudate nucleus could be a neural substrate for cognitive effects of early nutrition, we compared two groups of adolescents, assigned a Standard-or High-nutrient diet in the postnatal weeks after preterm birth. Groups had similar birth status and neonatal course. Scans and IQ data were obtained from 76 adolescents and volumes of several subcortical structures were calculated. The High-nutrient group had significantly larger caudate volumes and higher Verbal IQ (VIQ). Caudate volumes correlated significantly with VIQ in the Standardnutrient group only. Caudate volume was influenced by early nutrition and related selectively to VIQ in males, but not in females. Our findings may partly explain the effects of early diet on cognition and the predominant effects in males. They are among the first to show that human brain structure can be influenced by early nutrition.

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