A pedigree with autosomal dominant thrombocytopenia, red cell macrocytosis, and an occurrence of t(12:21) positive pre-B acute lymphoblastic leukemia

Sampling and analyzing new families with inherited blood disorders are major steps contributing to the identification of gene(s) responsible for normal and pathologic hematopoiesis. Familial occurrences of hematological disorders alone, or as part of a syndromic disease, have been reported, and for some the underlying genetic mutation has been identified. Here we describe a new autosomal dominant inherited phenotype of thrombocytopenia and red cell macrocytosis in a four-generation pedigree. Interestingly, in the youngest generation, a 2-year-old boy presenting with these familial features has developed acute lymphoblastic leukemia characterized by a t(12;21) translocation. Tri-lineage involvement of platelets, red cells and white cells may suggest a genetic defect in an early multiliear progenitor or a stem cell. Functional assays in EBV-transformed cell lines revealed a defect in cell proliferation and tubulin dynamics. Two candidate genes, RUNX1 and FOG1, were sequenced but no pathogenic mutation was found. Identification of the underlying genetic defect(s) in this family may help in understanding the complex process of hematopoiesis.

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease

BACKGROUND: Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kidney disease. We hypothesized that matrix and TBM degradation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal dominant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment on MMPs. METHODS: 5-week-old male heterozygous (Cy/+) and wild-type normal (+/+) rats were treated with sirolimus (2 mg/kg/day) through drinking water for 3 months. RESULTS: The mRNA and protein levels of MMP-2 and MMP-14 were markedly increased in the kidneys of heterozygous Cy/+ animals compared to wild-type +/+ as shown by RT-PCR and Western blot analyses for MMP-2 and MMP-14, and by zymography for MMP-2. Strong MMP-2 expression was detected by immunoperoxidase staining in cystic epithelial cells that also displayed an altered, thickened TBM. Tissue inhibitor of metalloproteinases-2 (TIMP-2) expression was not changed in Cy/+ kidneys. Sirolimus treatment leads to decreased protein expression of MMP-2 and MMP-14 in Cy/+, whereas MMP-2 and MMP-14 mRNA levels and TIMP-2 protein levels were not affected by sirolimus. CONCLUSION: In summary, in kidneys of the Han:SPRD rat model of ADPKD, there is a marked upregulation of MMP-2 and MMP-14. Sirolimus treatment was associated with a marked improvement of MMP-2 and MMP-14 overexpression, and this correlated also with less matrix and TBM alterations and milder cystic disease.

How do subordinate and dominant species in semi-natural mountain grasslands relate to productivity and land-use change?

Changes in agricultural practices of semi-natural mountain grasslands are expected to modify plant community structure and shift dominance patterns. Using vegetation surveys of 11 sites in semi-natural grasslands of the Swiss Jura and Swiss and French Alps, we determined the relative contribution of dominant, subordinate and transient plant species in grazed and abandoned communities and observed their changes along a gradient of productivity and in response to abandonment of pasturing. The results confirm the humpbacked diversity–productivity relationship in semi-natural grassland, which is due to the increase of subordinate species number at intermediate productivity levels. Grazed communities, at the lower or higher end of the species diversity gradient, suffered higher species loss after grazing abandonment. Species loss after abandonment of pasturing was mainly due to a higher reduction in the number of subordinate species, as a consequence of the increasing proportion of dominant species. When plant biodiversity maintenance is the aim, our results have direct implications for the way grasslands should be managed. Indeed, while intensification and abandonment have been accelerated since few decades, our findings in this multi-site analysis confirm the importance of maintaining intermediate levels of pasturing to preserve biodiversity.

Genomewide association for a dominant pigmentation gene in sheep

Most published genomewide association studies (GWAS) in sheep have investigated recessively inherited monogenic traits. The objective here was to assess the feasibility of performing GWAS for a dominant trait for which the genetic basis was already known. A total of 42 Manchega and Rasa Aragonesa sheep that segregate solid black or white coat pigmentation were genotyped using the SNP50 BeadChip. Previous analysis in Manchegas demonstrated a complete association between the pigmentation trait and alleles of the MC1R gene, setting an a priori expectation for GWAS. Multiple methods were used to identify and quantify the strength of population substructure between black and white animals, before allelic association testing was performed for 49 034 SNPs. Following correction for substructure, GWAS identified the most strongly associated SNP (s26449) was also the closest to the MC1R gene. The finding was strongly supported by the permutation tree-based random forest (RF) analysis. Importantly, GWAS identified unlinked SNP with only slightly lower p-values than for s26449. Random forest analysis indicated these were false positives, suggesting interpretation based on both approaches was beneficial. The results indicate that a combined analytical approach can be successful in studies where a modest number of animals are available and substantial population stratification exists.

Herbivores equalize the seedling height growth of three dominant tree species in an African tropical rain forest

Determining the impact of insect herbivores on forest tree seedlings and saplings is difficult without experimentation in the field. Moreover, this impact may be heterogeneous in time and space because of seasonal rainfall and canopy disturbances, or ‘gaps’, which can influence both insect abundance and plant performance. In this study we used fine netting to individually protect seedlings of Microberlinia bisulcata, Tetraberlinia bifoliolata and Tetraberlinia korupensis trees (Fabaceae = Leguminosae) from insects in 41 paired gap-understorey locations across 80 ha of primary rain forest (Korup, Cameroon). For all species, growth in height and leaf numbers was negligible in the understorey, where M. bisulcata had the lowest survival after c. 2 years. In gaps, however, all species responded positively with pronounced above-ground growth across seasons. When exposed to herbivores their seedling height growth was similar, but in the absence of herbivores, M. bisulcata significantly outgrew both Tetraberlinia species and matched their leaf numbers. This result suggests that insect herbivores might play an important role in maintaining species coexistence by mitigating sapling abundance of the more palatable M. bisulcata, which in gaps was eaten the most severely. The higher ratio in static leaf damage of control-to-caged M. bisulcata seedlings in gaps than understorey locations was consistent with the Plant Vigour Hypothesis. This result, however, did not apply to either Tetraberlinia species. For M. bisulcata and T. korupensis, but not T. bifoliolata (the most shade-tolerant species), caging improved relative seedling survival in the understory locations compared to gaps, providing restricted support for the Limiting Resource Model. Approximately 2.25 years after treatments were removed, the caged seedlings were taller and had more leaves than controls in all three species, and the effect remained strongest for M. bisulcata. We conclude that in this community the impact of leaf herbivory on seedling growth in gaps is strong for the dominant M. bisulcata, which coupled to a very low shade-tolerance contributes to limiting its regeneration. However, because gaps are common to most forests, insect herbivores may be having impacts upon functionally similar tree species that are also characterized by low sapling recruitment much more widely than currently appreciated. An implication for the restoration and management of M. bisulcata populations in forests outside of Korup is that physical protection from herbivores of new seedlings where the canopy is opened by gaps, or by harvesting, should substantially increase its subcanopy regeneration, and thus, too, its opportunities for adult recruitment.

Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59Delta/A60W) in the neurophysin moiety of prepro-vasopressin-neurophysin II (AVP-NP II).

OBJECTIVE To study clinical, morphological and molecular characteristics in a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). PARTICIPANTS AND METHODS A 15-month-old girl presenting with symptoms of polydipsia and polyuria was investigated by water deprivation test. Evaluation of the family revealed three further family members with symptomatic vasopressin-deficient diabetes insipidus. T1-weighted magnetic resonance images of the posterior pituitary were taken in two affected adult family members and molecular genetic analysis was performed in all affected individuals. RESULTS The water deprivation test in the 15-month-old child confirmed the diagnosis of vasopressin-deficient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in both adults with adFNDI. Direct sequence analysis revealed a new deletion (177-179DeltaCGC) in exon 2 of the AVP-NP II gene in all affected individuals. At the amino acid level, this deletion eliminates cysteine 59 (C59Delta) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precursor; interestingly, the remainder of the reading frame remains unchanged. According to the three-dimensional structure of neurophysin, C59 is involved in a disulphide bond with C65. CONCLUSIONS Deletion of C59 and substitution of A60W in the AVP-NP II precursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in line with the clinical and morphological findings in the reported family with adFNDI.