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Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.

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ABSTRACT Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.

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Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.

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A novel flavi-like virus tentatively named Diaphorina citri flavi-like virus (DcFLV) was identified in field populations of Diaphorina citri through small RNA and transcriptome sequencing followed by reverse transcription (RT)-PCR. We report here the complete nucleotide sequence and genome organization of DcFLV, the largest flavi-like virus identified to date.

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BACKGROUND: A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. METHODS: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. RESULTS: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2-12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11-25) generations ago. We infer a western European geographic origin of the shared haplotype. CONCLUSIONS: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.

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The subfamily Phyllomedusinae has attracted a great interest of many researchers mainly due to the high diversity of these frog species and plethora of pharmacological activities frequently observed for their skin secretions. Despite of this fact, mainly for new species, limited information is available regarding the molecular composition of these skin secretions and the cellular components involved in their production. Phyllomedusa nordestina is a recently described Brazilian frog species also popularly known as 'tree-frogs'. Aiming at contributing to the biological knowledge of this species, we show here the gene expression profile of this frog skin secretion using a global ESTs analysis of a cDNA library. The marked aspect of this analysis revealed a significant higher transcriptional level of the opioid peptide dermorphins in P. nordestina skin secretion than in Phyllomedusa hypochondrialis, which is its closest related species, belonging both to the same phylogenetic group. Precursors of bioactive peptides as dermaseptins, phylloseptins, tryptophyllins, and bradykinin-like peptideswere also found in this library. Transcripts encoding proteins related to ordinary cellular functions and pathways were also described. Some of them are chiefly involved in the production of the skin secretion. Taken together, the data reported here constitute a contribution to the characterization of the molecular diversity of gene-encoded polypeptides with potential possibility of pharmacological exploitation. The transcriptional composition of the skin secretion may also help to give the necessary support for the definition of P. nordestina as a new species, which actually relies basically on frog morphological characteristics and geographical distribution.

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The rudimentary characteristic of the eyes of fossorial animals raises some questions regarding its evolution and functionality. Would these eyes result from atrophy or from stagnated development? How would its visual function work? Anatomical investigations of these organs are the fundamental preamble to answer those questions, which are still little explored by the literature. In this article we have studied anatomical aspects of the eyes of three species of fossorial reptiles, within the suborder Amphisbaena (Amphisbaena alba, Amphisbaena mertensi, Leposternon infraorbitale), as well as a species within the ophidian suborder (Typhlops brongersmianus). The minuscule eyes (1-2 mm diameter) were visualized through a scale, a translucent area which corresponds to the spectacle. This spectacle is a thinner and transparent scale, covering a conjunctival sac. The retrobulbar space was filled with the harderian gland. The eyes of Typhlops presented an oval shape, whereas Amphisbaena specimens presented cup-shaped eyes. In Amphisbaenian sclera is comprised of cartilage, while the thin sclera of Typhlops consists of connective tissue and striated muscle fibers. The retina presented all the typical layers found in vertebrates, regardless the species. The characteristics involved in the fossil adaptation of these species include: reduced size of the eyeball, rudimentary cornea, absence of the anterior chamber, presence of a complex iris-ciliary body, and lens with amorphous nucleate cells. The analysis of the eye morphology of these animals suggests that there might be a specific function concerning light perception.

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Amphibian skin secretions are a source of potential new drugs with medical and biotechnological applications. Rich in peptides produced by holocrine-type serous glands in the integument, these secretions play different roles, either in the regulation of physiological skin functions or in the defense against predators or microorganisms. The aim of the present work was to identify novel peptides with bradykinin-like structure and/or activity present in the skin of Phyllomedusa nordestina. In order to achieve this goal, the crude skin secretion of this frog was pre-fractionated by solid phase extraction and separated by reversed-phase chromatography. The fractions were screened for low-molecular-mass peptides and sequenced by mass spectrometry. It was possible to identify three novel bradykinin-related peptides, namely: KPLWRL-NH2 (Pnor 3), RPLSWLPK (Pnor 5) and VPPKGVSM (Pnor 7) presenting vascular activities as assessed by intravital microscopy. Pnor 3 and Pnor 7 were able to induce vasodilation. On the other hand, Pnor 5 was a potent vasoconstrictor. These effects were reproduced by their synthetic analogues.

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Amphibian skin secretions are a source of potential new drugs with medical and biotechnological applications. Rich in peptides produced by holocrine-type serous glands in the integument, these secretions play different roles, either in the regulation of physiological skin functions or in the defense against predators or microorganisms. The aim of the present work was to identify novel peptides with bradykinin-like structure and/or activity present in the skin of Phyllomedusa nordestina. In order to achieve this goal, the crude skin secretion of this frog was pre-fractionated by solid phase extraction and separated by reversed-phase chromatography. The fractions were screened for low-molecular-mass peptides and sequenced by mass spectrometry. It was possible to identify three novel bradykinin-related peptides, namely: KPLWRL-NH2 (Pnor 3), RPLSWLPK (Pnor 5) and VPPKGVSM (Pnor 7) presenting vascular activities as assessed by intravital microscopy. Pnor 3 and Pnor 7 were able to induce vasodilation. On the other hand, Pnor 5 was a potent vasoconstrictor. These effects were reproduced by their synthetic analogues.(AU)

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Species of the genus Brachycephalus, have a snout-vent length of less than 18 mm and are believed to have evolved through miniaturization. Brachycephalus ephippium, is particularly interesting; because its entire skull is hyperossified, and the presacral vertebrae and transverse processes are covered by a dorsal shield. We demonstrate in this paper that, at the macroscopic level, a completely hyperossified skull and dorsal shield occur only in B. ephippium, but not in B. ferruginus, B. izechsohni, B. pernix, B. pombali, B. brunneus, B. didactylus, and B. hermogenesi. An intermediate condition, in which the skull is hyperossified but a dorsal shield is absent, occurs in B. vertebralis, B. nodoterga, B. pitanga, and B. alipioi. The microscopic structure of hyperossification was examined in skulls of B. ephippium and B. pitanga, revealing a complex organization involving the presence of Sharpey fibers, which in humans are characteristic of periodontal connections.

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Tupinambis merianae is a lizard of the Brazilian fauna and belongs to the Squamata order. Blood cell data are scarce. Blood samples from six specimens of adult T. merianae were used to evaluate some hematological parameters. For structural analysis, 2 ml of blood was collected in the presence of EDTA. Part of the blood was used for preparing blood smears which were submitted to the methods of Leishman, Laür, and toluidine blue, and the cytochemical reactions of periodic acid-Schiff, sirius red, sudan black B, and ortho-toluidine-H2 O2. The remainder was centrifuged and the leukocyte buffy coat was fixed in Karnovsky's fluid for electron microscopy examination. The following blood cells were identified: mature and immature erythrocytes, spherical and elliptical thrombocytes, heterophilic granulocytes, eosinophils and basophils types I and II, lymphocytes, monocytes, and azurophilic cells. The more significant results obtained were: the presence of glycogen in the cytoplasm of the thrombocytes, heterophils, and basophils; the presence of basic polyaminoacid-rich proteins in the granules of heterophils and eosinophils and myeloperoxidase in the granules of the heterophils, eosinophils, and azurophilic cells; and sudanophilic small granules in the heterophils, eosinophils, and azurophilic cells. More detailed morphological aspects of the cells were observed by means of ultrastructural analysis.

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Some anurans have a peculiar casqued head with the skin co-ossified with the underlying bones. This type of skull usually is associated with phragmosis, a protective behaviour in which the animal enters a hole and closes it with the head. Although co-ossification of the head in lissamphibians frequently has been associated with water economy, recent studies of Corythomantis greeningi, a casque-headed tree frog from semi-arid areas in north-eastern Brazil, suggest that cranial co-ossification contributes little to conservation of water in the frog. Instead, during phragmotic behaviour, the co-ossified head protects the animal against predators and indirectly enhances water balance. Thus, the primary role of co-ossification is defence, a hypothesis that is the focus of this study, which describes the morphology of the head of C. greeningi with an emphasis on the co-ossification and the venom glands. We report on behavioural features and on the toxicity of the cutaneous secretion produced by the abundant venom glands that are associated with large spicules on the skull.

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Amphibian skin is characterized by the presence of mucous glands, related to cutaneous breathing, reproduction and water balance, and granular glands, related to the production of toxins used in defence. In some species the granular glands can form accumulations in certain regions of the body. This is the case for inguinal macroglands of the leptodactylid frog Physalaemus nattereri, where these structures form a pair of black discs associated with deimatic behaviour. The morphology of the inguinal macroglands and their secretion were studied in this species and correlated to deimatic behaviour. The inguinal macroglands are formed from elongated granular glands that, in contrast with the granular glands of the rest of the skin, have small spherical granules with a proteinic content. In the dermis of the whole body, except for the inguinal macroglands and the inguinal region, a well-developed calcified dermal layer is observed. During deimatic behaviour these macroglands discourage a potential predator from attacking, but if visual cues are insufficient and the predator persists in the attack, a toxic secretion is eliminated in its mouth. This elimination is favoured by the absence of a calcified dermal layer in the macroglands, which makes the dermal region softer than the rest of the dorsal skin.

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Some species of anuran amphibians possess a calcified dermal layer (the Eberth-Kastschenko layer) located between the "stratum spongiosum" and the "stratum compactum." This layer consists of calcium phosphate deposits, proteoglycans, and glycosaminoglycans. Although regarded as a protective layer against desiccation, a calcium reservoir, or possibly a remnant of a dermal skeleton present in anuran ancestors, very little is known about its origin, structure, and function. Thus, we studied the structure and composition of the mineralized dermal layer of Corythomantis greeningi, a peculiar hylid from the Brazilian semiarid region (caatinga), using conventional and cryosubstitution methods combined with transmission, scanning, and analytical electron microscopy. Results show that the dermal layer consists of dense, closely juxtaposed, globular structures. Although the electron opacity of the globules was variable, depending on the type of preparation, crystal-like inclusions were present in all of them, as confirmed by dark field microscopy. Electron probe X-ray microanalysis showed calcium, phosphorus, and oxygen, and electron diffraction revealed a crystalline structure comparable to that of a hydroxyapatite.

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Some species of anuran amphibians possess a calcified dermal layer (the Eberth-Kastschenko layer) located between the "stratum spongiosum" and the "stratum compactum". This layer consists of calcium phosphate deposits, proteoglycans, and glycosaminoglycans. Although regarded as a protective layer against desiccation, a calcium reservoir, or possibly a remnant of a dermal skeleton present in anuran ancestors, very little is known about its origin, structure, and function. Thus, we studied the structure and composition of the mineralized dermal layer of Corythomantis greeningi, a peculiar hylid from the Brazilian semiarid region (caatinga), using conventional and cryosubstitution methods combined with transmission, scanning, and analytical electron microscopy. Results show that the dermal layer consists of dense, closely juxtaposed, globular structures. Although the electron opacity of the globules was variable, depending on the type of preparation, crystal-like inclusions were present in all of them, as confirmed by dark field microscopy. Electron probe X-ray microanalysis showed calcium, phosphorus, and oxygen, and electron diffraction revealed a crystalline structure comparable to that of a hydroxyapatite.

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The femoral or cloacal region of many species of lizards and amphisbaenians exhibits epidermal glands. The pores of these glands are plugged with holocrine solid secretions that serve as semiochemical sources. Many authors assume that these glands are mainly associated with reproduction and demarcation of territory. The structure of precloacal glands in Amphisbaena alba was previously studied by Antoniazzi et al. (Zoomorphology 113:199-203, 1993; J. Morphol. 221:101-109, 1994). These authors suggested that as the animal moves inside tunnels, the secretion plugs are abraded against the substrate, releasing a secretion trail. Some aspects of the plug were difficult to interpret in fine sections due to the dense and brittle nature of the plug. The morphology of the trail, and the manner of deposition on the substrate, have never been reported. This study presents a primarily scanning electron microscopic description of A. alba precloacal glands and of the secretion plugs. It also demonstrates experimentally the formation of the trail and its fine morphology. The results show that when the plugs scrape against the substrate, their constitution helps them to fragment into tiny pieces, which are spread on the ground, thus forming a trail. Each one of the fragments corresponds to a secretion granule of the precloacal gland's secretory cells. In this way, the trail might have an extensive area for volatilization of semiochemicals, constituting an efficient means of intraspecific communication inside the tunnels.

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The caecilians (or Gymnophiona) constitute one of the least well known groups of terrestrial vertebrates because most species live underground, in quite unaccessible environments. Siphonops annulatus is an exclusively fossorial species and is the most extensively distributed caecilian in South America. This work is the first of a series which intends to study the complete morphology of this species. It describes the general anatomy and the initial portion of the digestive system, from the mouth to the stomach. The general aspect of the body and the elongation of the organs seem to be related to adaptation to the fossorial environment.

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