Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from -21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 'high' and 19 'low' animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the 'risk' genotypes from these three loci was detected, with an increasing number of 'risk' genotypes associated with a blunted ACTH response (P = 0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.

Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.

Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice. Dominant disorders, possibly allelic to the recessive loci, are seen in both species (ED3, Dlslk). A candidate gene has recently been identified at the dl locus that is mutated in both dl and Dlslk mutant alleles. We isolated and characterized its human DL homologue, and identified mutations in three families displaying recessive inheritance and two with dominant inheritance. The disorder does not map to the candidate gene locus in all autosomal recessive families, implying the existence of at least one additional human locus. The putative protein is predicted to have a single transmembrane domain, and shows similarity to two separate domains of the tumour necrosis factor receptor (TNFR) family.

Behavioral measures of vowel sensitivity in Mongolian gerbils (Meriones unguiculatus): effects of age and genetic origin.

Absolute thresholds for complex vowel stimuli were compared in Mongolian gerbils (Meriones unguiculatus) as a function of age and genetic origin. For a group of 12-month-old 'domestic' gerbils obtained from Tumblebrook Farms, lowest thresholds averaging 14 dB SPL occurred for the vowel /alpha/, which had its most intense formant (F1) at 730 Hz. Thresholds increased to 22 dB SPL for /i/, which had its two most intense formants (F1 and F3) at 270 and 3000 Hz, respectively. Highest thresholds of 30 dB SPL occurred for /u/, which had its most intense formant (F1) at 300 Hz. Thresholds increased by about 10 dB per year through the ages of 12-36 months, with most of the loss occurring for /alpha/ and /u/. The domestic gerbils' /alpha/ thresholds corresponded well to those measured in aging gerbils in electrophysiological studies. Vowel thresholds were also measured in a group of first-generation offspring of 'wild' gerbils imported from Asia, first tested at the ages of 18-24 months. Thresholds were similar to those of the 12-month-old domestic gerbils, and showed no hearing loss with age up to 36 months. The wild gerbils were also free of ear impactions, which commonly occurred in the domestic gerbils. The hearing loss with age in the domestic gerbils may have a genetic basis, and might be due to inbreeding in the domestic strain, in contrast to the hybrid vigor of the wild gerbils.

Anatomical and gravitational influences on cardiac displacement in snakes (Lepidosauria, Serpentes).

Radiographs of live, unanesthetized snakes were used to document the position of the heart in the body cavity during horizontal, head-up, and head-down postures. The extent of cardiac displacement observed during these postural changes differed substantially among the snakes examined, ranging from virtually none in a thin-bodied arboreal snake to as much as three vertebral lengths (= half the length of the heart) in a heavy-bodied terrestrial Crotalus. The basis of this differential cardiac displacement is attributed to the anatomical "packaging" of the pericardial sac. In some snakes the pericardial sac is loosely suspended in the body cavity by the great vessels and connective tissue sheets. In contrast, in other snakes the pericardical sac is buttressed against the body wall, the lung, or the liver. We hypothesize that cardiac displacement during postural change may alter the pattern of blood flow in the aortae of snakes.