👤 Petr Novák

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m Show less

The size of a cell sets the scale for all biochemical processes within it, thereby affecting cellular fitness and survival. Hence, cell size needs to be kept within certain limits and relatively constant over multiple generations. However, how cells measure their size and use this information to regulate growth and division remains controversial. Here, we present two mechanistic mathematical models of the budding yeast (S. cerevisiae) cell cycle to investigate competing hypotheses on size control: inhibitor dilution and titration of nuclear sites. Our results suggest that an inhibitor-dilution mechanism, in which cell growth dilutes the transcriptional inhibitor Whi5 against the constant activator Cln3, can facilitate size homeostasis. This is achieved by utilising a positive feedback loop to establish a fixed size threshold for the Start transition, which efficiently couples cell growth to cell cycle progression. Yet, we show that inhibitor dilution cannot reproduce the size of mutants that alter the cell's overall ploidy and WHI5 gene copy number. By contrast, size control through titration of Cln3 against a constant number of genomic binding sites for the transcription factor SBF recapitulates both size homeostasis and the size of these mutant strains. Moreover, this model produces an imperfect 'sizer' behaviour in G1 and a 'timer' in S/G2/M, which combine to yield an 'adder' over the whole cell cycle; an observation recently made in experiments. Hence, our model connects these phenomenological data with the molecular details of the cell cycle, providing a systems-level perspective of budding yeast size control. Show less

We present a case study of an elderly woman with systemic lambda-type AL amyloidosis that featured unusually extensive cutaneous involvement. The case initially presented with a sudden hyper β-carotenemia with carotenoderma that instigated the clinical examination including skin biopsy. A diagnosis of systemic amyloidosis was made. Immunohistochemistry and Western-blot analysis indicated the presence of lambda light chain proteins in skin amyloid deposits. However, notable co-deposition of wild-type apoA-I and transthyretin was observed which caused initial diagnostic confusion. Proteomic analysis of microdissected skin amyloid deposits by mass spectrometry confirmed lambda light chain proteins in amyloid deposits and co-deposition of apolipoprotein A-IV and serum amyloid P-component. The patient died from renal failure caused by amyloid nephropathy combined with analgesic nephropathy. The autopsy disclosed vascular, cardiac, renal and pulmonary amyloid deposition. While all amyloid deposits were positive for lambda light chain proteins, the immunodetection of apoA-I and transthyretin varied significantly among the visceral amyloid deposits. Although the patient exhibited a 1000-fold increase in serum β-carotene levels, only a mild increase in retinol and lutein concentrations was observed. Increased β-carotene values were also found in the liver and the skin. The mechanisms underlying this hyper β-carotenemia remain undetermined. Show less

Endocrine ophthalmopathy is a chronic eye disease, characterized by inflammation in parabulbar and retrobulbar space, occurring usually in Graves' thyrotoxicosis. Although the pathogenesis of the disease has not been clarified until now, it is accepted that this disease is of an autoimmune nature, where the targets of the autoimmune reaction are the antigens shared by thyroid and orbit-tissue. The autoantibodies against recombinant 1D protein are highly specific and sensitive for the diagnosis of endocrine orbitopathy. The aim of our study was to establish, whether the autoantibodies against 1D protein are found predominantly in patients with clinically expressed endocrine orbitopathy. We evaluated in 30 patients with clinically expressed endocrine orbitopathy the thickness of the three retrobulbar eye muscles, damaged by endocrine orbitopathy, determined the parameters of thyroid hormones and anti-TSH receptor autoantibodies. In all patients the detection of circulating autoantibodies against recombinant 1D protein was performed. Autoantibodies against recombinant 1D protein were found in all patients with clinically expressed endocrine orbitopathy. Immunoreactivity did not depend on the duration or severity of the eye disease, neither on patients' age. We did not find any correlation between the thickness of eye muscles and the titre of anti-TSH receptor autoantibodies, levels of ssTSH and free thyroxine and also any correlation between the thickness of eye muscles and the disease duration. Show less