A novel ECM1\it ECM1 splice site mutation in lipoid proteinosis

Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in $\it ECM1$. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the $\it ECM1$ gene and summarize the current knowledge on $\it ECM1$ mutations and possible genotype-phenotype correlations

Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS\textit {SCA8, SCA10, SCA12, SCA36, FXTAS} and C9orf72\it C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes

$\textbf {Background:}$ Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like $\textit {SCA8, SCA10, SCA12}$ and $\it {SCA36}$. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the $\it C9orf72$ gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. $\textbf {Methods:}$ We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the $\it C9orf72$ gene. $\textbf {Results:}$ Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in $\it C9orf72$. The analysis of the fragile X mental retardation 1 gene $\textit {(FMR1)}$ revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). $\textbf {Conclusions:}$ Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller $\it FMR1$ gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for $\it C9orf72$ expansion in ataxia patients

Endocannabinergic modulation of central serotonergic activity in healthy human volunteers

$\bf Background$ The serotonergic and the endocannabinoid system are involved in the etiology of depression. Depressive patients exhibit low serotonergic activity and decreased level of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2AG). Since the cannabinoid (CB) 1 receptor is activated by endogenous ligands such as AEA and 2AG, whose concentration are controlled by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively, we investigated the effects on serotonergic utilization. In this study, we investigated the impact of the rs1049353 single-nucleotide polymorphism (SNP) of the cannabinoid receptor 1 $\it (CNR1)$ gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the $\it FAAH$ gene on the serotonergic and endocannabinoid system in 59 healthy volunteers. $\bf Methods$ Serotonergic activity was measured by loudness dependence of auditory-evoked potentials (LDAEP). Plasma concentrations of AEA, 2AG and its inactive isomer 1AG were determined by mass spectrometry. Genotyping of two SNPs $\textit {(rs1049353, rs344420)}$ was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method. $\bf Results$ Genotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the $\it CNR1$-A-allele-carriers, a reduced AEA (A-allele-carrier $\textit {M = 0.66}$, SD = $\it 0.24$; GG genotype $\textit {M = 0.72}$, SD = $\it 0.24$) and 2AG (A-allele-carriers $\textit {M = 0.70}$, SD = $\it 0.33$; GG genotype M = 1.03, SD = $\it 0.83$) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed. $\bf Conclusions$ Our results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression

Homozygosity mapping and sequencing identify two genes that might contribute to pointing behavior in hunting dogs

$\textbf{Background:}$ The domestic dog represents an important model for studying the genetics of behavior. In spite of technological advances in genomics and phenomics, the genetic basis of most specific canine behaviors is largely unknown. Some breeds of hunting dogs exhibit a behavioral trait called "pointing" (a prolonged halt of movement to indicate the position of a game animal). Here, the genomes of pointing dogs (Large Munsterlander and Weimaraner) were compared with those of behaviorally distinct herding dogs (Berger des Pyrenées and Schapendoes). We assumed (i) that these four dog breeds initially represented inbred populations and (ii) that selective breeding for pointing behavior promotes an enrichment of the genetic trait in a homozygous state. $\textbf{Results:}$ The homozygosity mapping of 52 dogs (13 of each of the four breeds) followed by subsequent intervalresequencing identified fixed genetic differences on chromosome 22 between pointers and herding dogs. In addition, we identified one non-synonomous variation in each of the coding genes $\textit{SETDB2}$ and $\textit{CYSLTR2}$ that might have a functional consequence. Genetic analysis of additional hunting and non-hunting dogs revealed consistent homozygosity for these two variations in six of seven pointing breeds. $\textbf{Conclusions:}$ Based on the present findings, we propose that, together with other genetic, training and/or environmental factors, the nucleotide and associated amino acid variations identified in genes $\textit{SETDB2}$ and $\textit{CYSLTR2}$ contribute to pointing behavior

Cholecystokinin A receptor (CCKAR) gene variation is associated with language lateralization

Schizophrenia is a psychiatric disorder associated with atypical handedness and language lateralization. However, the molecular mechanisms underlying these functional changes are still poorly understood. Therefore, the present study was aimed at investigating whether variation in schizophrenia-related genes modulates individual lateralization patterns. To this end, we genotyped 16 single nucleotide polymorphisms that have previously been linked to schizophrenia on a meta-analysis level in a sample of 444 genetically unrelated healthy participants and examined the association of these polymorphisms with handedness, footedness and language lateralization. We found a significant association of the cholecystokinin-A receptor $\textit {(CCKAR)}$ gene variation rs1800857 and language lateralization assessed using the dichotic listening task. Individuals carrying the schizophrenia risk allele C of this polymorphism showed a marked reduction of the typical left-hemispheric dominance for language processing. Since the cholecystokinin A receptor is involved in dopamine release in the central nervous system, these findings suggest that genetic variation in this receptor may modulate language lateralization due to its impact on dopaminergic pathways

PCSK6\it PCSK6 VNTR polymorphism is associated with degree of handedness but not direction of handedness

Although the left and right human cerebral hemispheres differ both functionally and anatomically, the mechanisms that underlie the establishment of these hemispheric specializations, as well as their physiological and behavioral implications, remain largely unknown. Since cerebral asymmetry is strongly correlated with handedness, and handedness is assumed to be influenced by a number of genetic and environmental factors, we performed an association study of $\it LRRTM1$ rs6733871 and a number of polymorphisms in $\it PCSK6$ and different aspects of handedness assessed with the Edinburgh handedness inventory in a sample of unrelated healthy adults (n = 1113). An intronic 33bp variable-number tandem repeat (VNTR) polymorphism in PCSK6 (rs10523972) shows a significant association (significance threshold: p<0.0025, adjusted for multiple comparisons) with a handedness category comparison ($\it P$ = 0.0005) and degree of handedness ($\it P$ = 0.001). These results provide further evidence for the role of $\it PCSK6$ as candidate for involvement in the biological mechanisms that underlie the establishment of normal brain lateralization and thus handedness and support the assumption that the degree of handedness, instead the direction, may be the more appropriate indicator of cerebral organization

SOX9\it SOX9 duplication linked to intersex in deer

A complex network of genes determines sex in mammals. Here, we studied a European roe deer with an intersex phenotype that was consistent with a XY genotype with incomplete male-determination. Whole genome sequencing and quantitative real-time PCR analyses revealed a triple dose of the $\it SOX9$ gene, allowing insights into a new genetic defect in a wild animal

Neurodegeneration in the olfactory bulb and olfactory deficits in the Ccdc66\it {Ccdc66} -/- mouse model for retinal degeneration

The $\it {Ccdc66}$-deficient ($\it {Ccdc66}$) mouse model exhibits slow progressive retinal degeneration. It is unclear whether $\it {Ccdc66}$ protein also plays a role in the wildtype (WT; $\it {Ccdc66}$ +/+) mouse brain and whether the lack of $\it {Ccdc66}$ gene expression in the $\it {Ccdc66}$ -/- mouse brain may result in morphological and behavioral alterations. $\it {Ccdc66}$ protein expression in different brain regions of the adult WT mouse and in whole brain during postnatal development was quantified by SDS-PAGE and Western blot. $\it {Ccdc66}$ reporter gene expression was visualized by X-gal staining. Selected brain regions were further analyzed by light and electron microscopy. In order to correlate anatomical with behavioral data, an olfactory habituation/dishabituation test was performed. $\it {Ccdc66}$ protein was expressed throughout the early postnatal development in the WT mouse brain. In adult mice, the main olfactory bulb exhibited high $\it {Ccdc66}$ protein levels comparable to the expression in the retina. Additionally, the $\it {Ccdc66}$ -/- mouse brain showed robust $\it {Ccdc66}$ reporter gene expression especially in adult olfactory bulb glomeruli, the olfactory nerve layer and the olfactory epithelium. Degeneration was detected in the $\it {Ccdc66}$ -/- olfactory bulb glomeruli at advanced age. This degeneration was also reflected in behavioral alterations; compared to the WT, $\it {Ccdc66}$ -/- mice spent significantly less time sniffing at the initial presentation of unknown, neutral odors and barely responded to social odors. $\it {Ccdc66}$ -/- mice develop substantial olfactory nerve fiber degeneration and alteration of olfaction-related behavior at advanced age. Thus, the $\it {Ccdc66}$ -/- mouse model for retinal degeneration adds the possibility to study mechanisms of central nervous system degeneration

A large deletion in RPGR\it RPGR causes XLPRA in Weimaraner dogs

$\textbf {Background:}$ Progressive retinal atrophy (PRA) belongs to a group of inherited retinal disorders associated with gradual vision impairment due to degeneration of retinal photoreceptors in various dog breeds. PRA is highly heterogeneous, with autosomal dominant, recessive or X-linked modes of inheritance. In this study we used exome sequencing to investigate the molecular genetic basis of a new type of PRA, which occurred spontaneously in a litter of German short-hair Weimaraner dogs. $\textbf {Results:}$ Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator $\textit {(RPGR)}$ gene known to be involved in human retinitis pigmentosa and canine PRA. Screening of 16 individuals in the corresponding pedigree of short-hair Weimaraners by qPCR, verified the deletion in hemizygous or heterozygous state in one male and six female dogs, respectively. The mutation was absent in 88 additional unrelated Weimaraners. The deletion was not detectable in the parents of one older female which transmitted the mutation to her offspring, indicating that the $\it RPGR$ deletion represents a $\textit {de novo}$ mutation concerning only recent generations of the Weimaraner breed in Germany. $\textbf {Conclusion:}$ Our results demonstrate the value of an existing DNA biobank combined with exome sequencing to identify the underlying genetic cause of a spontaneously occurring inherited disease. Identification of the genetic cause has allowed the development of a diagnostic test, which should help to eradicate the PRA causing mutation from the respective canine line. Thus, planning of future pairings is facilitated and manifestation of this type of PRA can be prevented

Handedness and the X chromosome

Prenatal androgen exposure has been suggested to be one of the factors influencing handedness, making the androgen receptor gene (AR) a likely candidate gene for individual differences in handedness. Here, we examined the relationship between the length of the CAG-repeat in AR and different handedness phenotypes in a sample of healthy adults of both sexes (n = 1057). Since AR is located on the X chromosome, statistical analyses in women heterozygous for CAG-repeat lengths are complicated by X chromosome inactivation. We thus analyzed a sample of women that were homozygous for the CAG-repeat length (n = 77). Mixed-handedness in men was significantly associated with longer CAG-repeat blocks and women homozygous for longer CAG-repeats showed a tendency for stronger left-handedness. These results suggest that handedness in both sexes is associated with the AR CAG-repeat length, with longer repeats being related to a higher incidence of non-right-handedness. Since longer CAG-repeat blocks have been linked to less efficient AR function, these results implicate that differences in AR signaling in the developing brain might be one of the factors that determine individual differences in brain lateralization