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Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.

ABSTRACT: Erythropoietin regulates the proliferation and differentiation of erythroid precursor cells. Its effect is mediated by the erythropoietin receptor (EPOR), a member of a large family of cytokine receptors. The EPOR gene has recently been cloned, sequenced, and characterized. As shown experimentally, its intracellular C-terminal part contains a domain exerting negative control on erythropoiesis. Here we describe a G to A transition in nucleotide 6002 of the EPOR gene that converts a TGG codon for tryptophan into a TAG stop codon, predicting the truncation of the 70 C-terminal amino acids of the EPOR molecule. The mutation occurs in heterozygous form in the germ-line DNA of members of a large kindred in which primary erythrocytosis is segregating as a mild autosomal dominant trait. The mutation cosegregates with the disease phenotype in all 29 affected family members studied; it occurs in no unaffected family members or unrelated controls. This appears to be an example of a human condition caused by an EPOR mutation. Striking similarities exist between the human phenotype described here and phenotypes of cell lines expressing similarly truncated EPOR molecules produced experimentally. By analogy with these in vitro studies, one can hypothesize that the truncated EPOR molecules are activated by suppression of phosphorylation leading to loss of the down-modulation exerted by intact EPOR molecules. Experimental modifications of the EPOR gene may eventually have therapeutic applications.

SUBMITTER: de la Chapelle A

PROVIDER: S-EPMC46538 | biostudies-other | 1993 May

REPOSITORIES: biostudies-other

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Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.

de la Chapelle A A Träskelin A L AL Juvonen E E

Proceedings of the National Academy of Sciences of the United States of America 19930501 10

Erythropoietin regulates the proliferation and differentiation of erythroid precursor cells. Its effect is mediated by the erythropoietin receptor (EPOR), a member of a large family of cytokine receptors. The EPOR gene has recently been cloned, sequenced, and characterized. As shown experimentally, its intracellular C-terminal part contains a domain exerting negative control on erythropoiesis. Here we describe a G to A transition in nucleotide 6002 of the EPOR gene that converts a TGG codon for ...[more]

PMID: 8506290

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Project description:See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.

Project description:BackgroundThe order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.MethodsIn this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.ResultsConcentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.ConclusionsWe found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

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Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.

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Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.

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