A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies

Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4)

BACKGROUND: Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds. RESULTS: We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families. CONCLUSION: We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly

The bovine aristaless-like homeobox 4 (ALX4) as a candidate gene for syndactyly

The ALX4 (aristaless-like homeobox 4) gene encodes a paired-type homeodomain transcriptional activator and plays a major role in anterior-posterior pattern formation during limb development. Here, the cloning, genomic structure and expression of the bovine ortholog of the ALX4 gene are reported. The bovine ALX4 gene consists of four exons and is located on BTA15q28-->q29 in a region syntenic to HSA11p11.2. The transcribed ALX4 mRNA encodes a 397-amino-acid protein showing a paired-type homeodomain and a C-terminal stretch of amino acids known as the OAR- or aristaless domain. The predicted protein shares 92.5% identity to human and mouse ALX4 proteins and all three species share almost complete identity in the conserved domains. ALX4 expression was detected by reverse transcriptase polymerase chain reaction in bovine fetal limb bones. The ALX4 gene was evaluated as a candidate gene for bovine syndactyly which has been mapped on the telomeric region of cattle chromosome 15. Sequencing of the four exons with flanking sequences of the bovine ALX4 gene from a panel of 14 affected animals belonging to German Holstein, German Fleckvieh and crossbreds, and 27 unaffected individuals from German Holstein revealed five silent SNPs within the coding region out of eleven SNPs in total. Four SNPs were polymorphic in the affected animals, but in comparison to the genotyped unaffected individuals the genotype distribution showed no evidence for an association to the phenotype. Therefore our data indicate that the ALX4 gene can probably be excluded as candidate gene for bovine syndactyly in the examined animals

Linkage of bilateral convergent strabismus with exophthalmus (BCSE) to BTA5 and BTA18 in German Brown cattle.

Bilateral convergent strabismus with exophthalmus (BCSE) is a widespread inherited eye defect in several cattle populations. Its progressive condition often leads to blindness in affected cattle and decreases their usability. Furthermore, the German animal welfare laws prevent breeding with animals whose progeny are expected to be affected by genetic defects. Identifying genes involved in the heredity of BCSE should lead to insights into the molecular pathogenesis of this eye disease and permit the establishment of a genetic test for this disease. A whole-genome scan for 10 families containing a total of 159 genotyped individuals identified two BCSE loci. One BCSE locus mapped to the centromeric region on bovine chromosome (BTA) 5 and the other BCSE locus mapped to the telomeric region of BTA18. Thus, it is possible that two genes are involved in the development of BCSE. Alternatively, one of these loci could be the cause for the development of BCSE and the other locus could affect the progression and severity of the defect

Childhood Maltreatment, Borderline Personality Features, and Coping as Predictors of Intimate Partner Violence

Intimate partner violence (IPV) is a serious mental and physical health concern worldwide. Although previous research suggests that childhood maltreatment increases the risk for IPV, the underlying psychological mechanisms of this relationship are not yet entirely understood. Borderline personality (BP) features may play an important role in the cycle of violence, being associated with interpersonal violence in both childhood and adult relationships. The present study investigated whether BP features mediate the relationship between childhood maltreatment and IPV, differentiating between perpetration and victimization, and taking maladaptive stress coping and gender into account. Self-reports on IPV, childhood trauma, BP features, and maladaptive stress coping were collected in a mixed (nonclinical and clinical) sample of 703 adults (n = 537 female, n = 166 male), using an online survey. A serial mediation analysis (PROCESS) was performed to quantify the direct effect of childhood maltreatment on IPV and its indirect effects through BP features and maladaptive coping. Childhood maltreatment severity significantly positively predicted IPV perpetration as well as victimization. BP features, but not coping, partially mediated this relationship. Follow-up analyses suggest that affective instability and interpersonal disturbances (e.g., separation concerns) play an important role in IPV perpetration, while interpersonal and identity disturbances may mediate the effect of childhood maltreatment on IPV victimization. In clinical practice, attention should be paid not only to histories of childhood abuse and neglect but also to BP features, which may be possible risk factors for IPV.Stress and Psychopatholog