Multiple QTLs linked to agro-morphological and physiological traits related to drought tolerance in potato.

Dissection of the genetic architecture of adaptation and abiotic stress-related traits is highly desirable for developing drought-tolerant potatoes and enhancing the resilience of existing cultivars, particularly as agricultural production in rain-fed areas may be reduced by up to 50 % by 2020. The “DMDD” potato progeny was developed at International Potato Center (CIP) by crossing the sequenced double monoploid line DM and a diploid cultivar of the Solanum tuberosum diploid Andigenum Goniocalyx group. Recently, a high-density integrated genetic map based on single nucleotide polymorphism (SNP), diversity array technology (DArT), simple sequence repeats (SSRs), and amplified fragment length polymorphism (AFLP) markers was also made available for this population. Two trials were conducted, in greenhouse and field, for drought tolerance with two treatments each, well-watered and terminal drought, in which watering was suspended 60 days after planting. The DMDD population was evaluated for agro-morphological and physiological traits before and after initiation of stress, at multiple time points. Two dense parental genetic maps were constructed using published genotypic data, and quantitative trait locus (QTL) analysis identified 45 genomic regions associated with nine traits in well-watered and terminal drought treatments and 26 potentially associated with drought stress. In this study, the strong influence of environmental factors besides water shortage on the expression of traits and QTLs reflects the multigenic control of traits related to drought tolerance. This is the first study to our knowledge in potato identifying QTLs for drought-related traits in field and greenhouse trials, giving new insights into genetic architecture of drought-related traits. Many of the QTLs identified have the potential to be used in potato breeding programs for enhanced drought tolerance

Hypoparathyroidism in an Egyptian child with Hutchinson-Gilford progeria syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hutchinson-Gilford progeria syndrome is a rare genetic disorder. It is reported to be present in one in eight million and is characterized by severe growth failure, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, early atherosclerosis and facial features that resemble those of an aged person. Apart from diabetes mellitus, there are no reported abnormalities of thyroid, parathyroid, pituitary or adrenal function. Here, we report the case of a 10-year-old Egyptian child with Hutchinson-Gilford progeria syndrome and hypoparathyroidism.</p> <p>Case presentation</p> <p>A 10-year-old Egyptian boy was referred to our institution for an evaluation of recurrent attacks of muscle cramps, paresthesia of his fingertips and perioral numbness of two months duration. On examination, we found dilated veins present over his scalp with alopecia and frontal bossing, a beaked nose, thin lips, protruding ears, a high pitched voice with sparse hair over his eyebrows and eyelashes and micrognathia but normal dentition. His eyes appeared prominent and our patient appeared to have poor sexual development. A provisional diagnosis of progeria was made, which was confirmed by molecular genetics study. Chvostek's and Trousseau's signs were positive. He had low total calcium (5.4 mg/dL), low ionized calcium (2.3 mg/dL), raised serum phosphate (7.2 mg/dL), raised alkaline phosphatase (118 U/L) and low intact parathyroid hormone (1.2 pg/mL) levels. He was started on oral calcium salt and vitamin D; his symptoms improved with the treatment and his serum calcium, urinary calcium and alkaline phosphates level were monitored every three months to ensure adequacy of therapy and to avoid hypercalcemia.</p> <p>Conclusion</p> <p>Routine checking of serum calcium, phosphorus and parathyroid hormone will help in the early detection of hypoparathyrodism among children with progeria.</p

Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging

Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24

The proteolytic maturation of the nuclear protein lamin A by the zinc metalloprotease ZMPSTE24 is critical for human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif), followed by ZMPSTE24-mediated cleavage of the last 15 amino acids, including the modified C-terminus. Failure to cleave the prelamin A "tail", due to mutations in either prelamin A or ZMPSTE24, results in a permanently prenylated form of prelamin A that underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and related progeroid disorders.Here we have investigated the features of the prelamin A substrate that are required for efficient cleavage by ZMPSTE24. We find that the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647) that interfere with efficient cleavage of the prelamin A tail; these mutations include R644C, L648A and N650A, in addition to the previously reported L647R. Our data suggests that 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, as they can be replaced by the 9 amino acid HA epitope. However, duplication of the same 9 amino acids (to increase the distance between the prenyl group and the cleavage site) impairs the ability of ZMPSTE24 to cleave prelamin A.Our data reveals amino acid preferences flanking the ZMPSTE24 cleavage site of prelamin A and suggests that spacing from the farnesyl-cysteine to the cleavage site is important for optimal ZMPSTE24 cleavage. These studies begin to elucidate the substrate requirements of an enzyme activity critical to human health and longevity

Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNAK542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe