Congenital analbuminaemia: Molecular defects and biochemical and clinical aspects

Background

DNA and mRNA sequencing of the coding regions of the human albumin gene (ALB) and of its intron/exon junctions has revealed twenty-one different molecular defects causing congenital analbuminaemia (CAA).

Scope of review

To describe the mutations in molecular terms and to present the current knowledge about the most important biochemical and clinical effects of CAA.

Major conclusions

CAA is rare, but its frequency seems to be significantly higher in restricted and minimally admixed populations. The condition affects especially the lipid metabolism but apart from a possible increased risk for atherosclerotic complications, it is generally associated with mild clinical symptoms in adults. By contrast, several reports indicate that analbuminaemic individuals may be at risk during the perinatal and childhood periods, in which they seem to show increased morbidity and mortality. The twenty-one causative defects include seven nonsense mutations, seven changes affecting splicing, five frame-shift/deletions, one frame-shift/insertion and one mutation in the start codon. These results indicate that the trait is an allelic heterogeneous disorder caused by homozygous (nineteen cases) or compound heterozygous (single case) inheritance of defects. Most mutations are unique, but one, named Kayseri, is responsible for about half of the known cases.

General significance

Study of the defects in the ALB resulting in CAA allows the identification of “hot spot” regions and contributes to understanding the molecular mechanism underlying the trait. Such studies could also give molecular information about different aspects of ALB regulation and shed light on the regulatory mechanisms involved in the synthesis of the protein. This article is part of a Special Issue entitled Serum Albumin.     

Noninvasive diffusive optical imaging of the auditory response to birdsong in the zebra finch

Songbirds communicate by learned vocalizations with concomitant changes in neurophysiological and genomic activities in discrete parts of the brain. Here, we tested a novel implementation of diffusive optical imaging (also known as diffuse optical imaging, DOI) for monitoring brain physiology associated with vocal signal perception. DOI noninvasively measures brain activity using red and near-infrared light delivered through optic fibers (optodes) resting on the scalp. DOI does not harm subjects, so it raises the possibility of repeatedly measuring brain activity and the effects of accumulated experience in the same subject over an entire life span, all while leaving tissue intact for further study. We developed a custom-made apparatus for interfacing optodes to the zebra finch (Taeniopygia guttata) head using 3D modeling software and rapid prototyping technology, and applied it to record responses to presentations of birdsong in isoflurane-anesthetized zebra finches. We discovered a subtle but significant difference between the hemoglobin spectra of zebra finches and mammals which has a major impact in how hemodynamic responses are interpreted in the zebra finch. Our measured responses to birdsong playback were robust, highly repeatable, and readily observed in single trials. Responses were complex in shape and closely paralleled responses described in mammals. They were localized to the caudal medial portion of the brain, consistent with response localization from prior gene expression, electrophysiological, and functional magnetic resonance imaging studies. These results define an approach for collecting neurophysiological data from songbirds that should be applicable to diverse species and adaptable for studies in awake behaving animals.     

Environmental-dependent proline accumulation in plants living on gypsum soils

Biosynthesis of proline—or other compatible solutes—is a conserved response of all organisms to different abiotic stress conditions leading to cellular dehydration. However, the biological relevance of this reaction for plant stress tolerance mechanisms remains largely unknown, since there are very few available data on proline levels in stress-tolerant plants under natural conditions. The aim of this work was to establish the relationship between proline levels and different environmental stress factors in plants living on gypsum soils. During the 2-year study (2009–2010), soil parameters and climatic data were monitored, and proline contents were determined, in six successive samplings, in ten taxa present in selected experimental plots, three in a gypsum area and one in a semiarid zone, both located in the province of Valencia, in south-east Spain. Mean proline values varied significantly between species; however, seasonal variations within species were in many cases even wider, with the most extreme differences registered in Helianthemum syriacum (almost 30 μmol g^?1 of DW in summer 2009, as compared to ca. 0.5 in spring, in one of the plots of the gypsum zone). Higher proline contents in plants were generally observed under lower soil humidity conditions, especially in the 2009 summer sampling preceded by a severe drought period. Our results clearly show a positive correlation between the degree of environmental stress and the proline level in most of the taxa included in this study, supporting a functional role of proline in stress tolerance mechanisms of plants adapted to gypsum. However, the main trigger of proline biosynthesis in this type of habitat, as in arid or semiarid zones, is water deficit, while the component of ‘salt stress’ due to the presence of gypsum in the soil only plays a secondary role.     

Metal Concentrations in Cerebrospinal Fluid and Blood Plasma from Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons. The cause of this degeneration is unknown, and different causal hypotheses include genetic, viral, traumatic and environmental mechanisms. In this study, we have analyzed metal concentrations in cerebrospinal fluid (CSF) and blood plasma in a well-defined cohort (n?=?17) of ALS patients diagnosed with quantitative electromyography. Metal analyses were performed with high-resolution inductively coupled plasma mass spectrometry. Statistically significant higher concentrations of manganese, aluminium, cadmium, cobalt, copper, zinc, lead, vanadium and uranium were found in ALS CSF compared to control CSF. We also report higher concentrations of these metals in ALS CSF than in ALS blood plasma, which indicate mechanisms of accumulation, e.g. inward directed transport. A pattern of multiple toxic metals is seen in ALS CSF. The results support the hypothesis that metals with neurotoxic effects are involved in the pathogenesis of ALS.     

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins,and serum cholesterol efflux capacity in cynomolgus monkeys

MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation.     

TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk.