Alfredo Ramirez

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Papers by Alfredo Ramirez

G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth

Nature Genetics, 2008

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Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Nature Genetics, 2006

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Effect of endogenous mutant and wild-type PINK1 on Parkin in fibroblasts from Parkinson disease patients

Human Molecular Genetics, 2010

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Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease

Nature Genetics, 2001

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Cloning and Characterization of SLC26A6, a Novel Member of the Solute Carrier 26 Gene Family

Genomics, 2001

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Nonmotor Symptoms in Genetic Parkinson Disease

Archives of Neurology, 2010

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A mutation in the signal sequence of LRP5 in a family with an osteoporosis-pseudoglioma syndrome (OPPG)-like phenotype indicates a novel disease mechanism for trinucleotide repeats

Human Mutation, 2009

We extend the spectrum of phenotypes caused by mutations in the Wnt/Norrin coreceptor low-density... more We extend the spectrum of phenotypes caused by mutations in the Wnt/Norrin coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) by identifying two novel types of mutation in related individuals whose presenting features were profound muscle hypotonia, mild mental retardation, blindness, and growth retardation. One mutation removes 6 out of 9 consecutive leucine residues in the LRP5 signal peptide (c.43_60del or p.Leu15_Leu20del), which impairs polypeptide entry into the endoplasmic reticulum (ER), trafficking to the cell membrane, and signal transduction. The second mutation resulted from nonhomologous recombination between Alu repeat sequences, which deleted exons 14–16 and would produce a nonfunctional, truncated, and frameshifted polypeptide, if expressed [chr11:g.(13871447_1387511)_(13879636_13879700)del (NW_925106.1) or p.Pro1010GlnfsX38]. We confirmed that the length of the LRP5 signal peptide poly-leucine repeat is polymorphic in the general population, and, importantly, we were able to demonstrate in independent in vitro assays that different allele sizes affect receptor processing and signal transduction. Consequently, this polymorphism may have physiologic effects in vivo. This latter finding is relevant since through a genomewide search we identified nearly 400 human proteins that contain poly-leucine repeats within their signal peptide. We chose 18 of these proteins and genotyped the underlying trinucleotide repeat in healthy Caucasian individuals. More than one length allele was observed in one-half of the proteins. We therefore propose that natural variation in poly-leucine-stretches within signal peptides constitutes a currently unrecognized source of variability in protein translation and expression. Hum Mutat 0, 1–8, 2009. © 2009 Wiley-Liss, Inc.

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Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D

Nature Genetics, 2001

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Association of Parkinson disease to PARK16 in a Chilean sample

Parkinsonism & Related Disorders, 2011

1. Parkinsonism Relat Disord. 2011 Jan;17(1):70-1. Epub 2010 Oct 8. Association of Parkinson dise... more

ATP13A2 variants in early-onset Parkinson's disease patients and controls

Movement Disorders, 2009

Four genes responsible for recessively inherited forms of Parkinson's disease (PD) have been iden... more Four genes responsible for recessively inherited forms of Parkinson's disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exons of the ATP13A2 coding region in 112 patients with early-onset PD (EOPD; <40 years) of mostly European ethnic origin and of 55 controls. We identified four carriers (3.6%) of novel single heterozygous ATP13A2 missense changes that were absent in controls. Interestingly, the carrier of one of these variants also harbored two mutations in the Parkin gene. None of the carriers had atypical features previously described in patients with two mutated ATP13A2 alleles (Kufor–Rakeb syndrome). Our data suggest that two mutated ATP13A2 alleles are not a common cause of PD. Although heterozygous variants are present in a considerable number of patients, they are—based on this relatively small sample—not significantly more frequent in patients compared to controls. © 2009 Movement Disorder Society

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Genetic association study of the P-type ATPase ATP13A2 in late-onset Parkinson's disease

Movement Disorders, 2009

A role of ATP13A2 in early-onset Parkinsonism (EOP) has been proposed. Conversely, the contributi... more A role of ATP13A2 in early-onset Parkinsonism (EOP) has been proposed. Conversely, the contribution of this ATPase to late-onset Parkinson's disease (PD) remains unexplored. We therefore conducted a case–control association study in this age-of-onset group with PD. The initial sample was of German origin and consisted of 220 patients with late-onset PD (mean age of onset 60.1 years) and 232 age-matched unrelated controls. Five single nucleotide polymorphisms (SNPs) covering ATP13A2 and its common haplotypes were genotyped. The overall association results in this sample were negative. Interestingly, gender stratification gave a positive result for SNP rs11203280 (PUNC = 0.016) in men. This result could not be reproduced in a replication sample of German and Serbian origin composed of 161 patients with late-onset PD (mean age of onset 51.7 years) and 150 age- and ethnic-matched controls. In conclusion, we found no consistent evidence for an association between ATP13A2 and late-onset PD. © 2008 Movement Disorder Society

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Rare missense variants in ATP1A2 in families with clustering of common forms of migraine

Human Mutation, 2005

Migraine is a recurrent neurovascular disease. Its two most common forms—migraine without aura (M... more Migraine is a recurrent neurovascular disease. Its two most common forms—migraine without aura (MO) and migraine with aura (MA)—both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na+/K+-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na+/K+-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine. Hum Mutat 26(4), 315–321, 2005. © 2005 Wiley-Liss, Inc.

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A Functional Dynein-Microtubule Network Is Required for NGF Signaling Through the Rap1/MAPK Pathway

Traffic, 2007

Rap1 transduces nerve growth factor (NGF)/tyrosine receptor kinase A (TrkA) signaling in early en... more Rap1 transduces nerve growth factor (NGF)/tyrosine receptor kinase A (TrkA) signaling in early endosomes, leading to sustained activation of the p44/p42 mitogen-activated protein kinases (MAPK1/2). However, the mechanisms by which NGF, TrkA and Rap1 are trafficked to early endosomes are poorly defined. We investigated trafficking and signaling of NGF, TrkA and Rap1 in PC12 cells and in cultured rat dorsal root ganglion (DRG) neurons. Herein, we show a role for both microtubule- and dynein-based transport in NGF signaling through MAPK1/2. NGF treatment resulted in trafficking of NGF, TrkA and Rap1 to early endosomes in the perinuclear region of PC12 cells where sustained activation of MAPK1/2 was observed. Disruption of microtubules with nocodazole in PC12 cells had no effect on the activation of TrkA and Ras. However, it disrupted intracellular trafficking of TrkA and Rap1. Moreover, NGF-induced activation of Rap1 and sustained activation of MAPK1/2 were markedly suppressed. Inhibition of dynein activity through overexpression of dynamitin (p50) blocked trafficking of Rap1 and the sustained phase of MAPK1/2 activation in PC12 cells. Remarkably, even in the continued presence of NGF, mature DRG neurons that overexpressed p50 became atrophic and most (>80%) developing DRG neurons died. Dynein- and microtubule-based transport is thus necessary for TrkA signaling to Rap1 and MAPK1/2.

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Is the addition of ECG gating to technetium-99m sestamibi SPET of value in the assessment of myocardial viability

European Journal of Nuclear Medicine, 1996

The main goal of this study was to evaluate whether the addition of ECG gating to technetium-99m ... more The main goal of this study was to evaluate whether the addition of ECG gating to technetium-99m sestamibi single-photon emission tomography (SPET) perfusion imaging assists the prediction of recovery of regional wall motion abnormalities after revascularization. Thirty-six patients with coronary artery disease were included in the study. All had wall motion abnormalities, and 31 (86%) had a clinical history of myocardial infarction. Coronary artery bypass surgery was performed in 18 patients and angioplasty in the remainder. All underwent ECG-gated and non-gated SPET at rest and after intravenous dipyridamole. Two-dimensional echocardiography was performed at a mean of 27 days before revascularization and at a mean of 69 days following revascularization to assess segmental wall motion changes. Perfusion prior to revascularization was analysed qualitatively and quantitatively on gated and non-gated SPET, and the results compared with those of echocardiography. Bullseye parameters were obtained from a normal database, generated from data in 40 normal volunteers, using dipyridamole ECG-gated and non-gated sestamibi SPET. There was good concordance between gated and non-gated qualitative analysis (79% with kappa=0.65) for normal, viable or necrotic segments. Gated SPET predicted functional recovery in 27 of 35 (77%) segments showing echocardiographic improvement while non-gated SPET did so in 30 of 39 (77%) such segments. Gated SPET predicted no functional recovery in 20 of 45 (44%) segments that did not show improved wall motion after revascularization, while with non-gated SPET the figure was 18 of 51 (35%). The positive predictive values of gated and non-gated SPET with regard to the recovery of wall motion following revascularization were 52% and 48%, while the negative predictive values were 71% and 67%, respectively.99mTc-sestamibi had a low predictive value for recovery of function if visual assessment was used in the analysis of SPET data. Quantitative bullseye sestamibi parameters (defect extension and severity, reversibility and percentage change in extension), from gated or non-gated studies, appear best to distinguish which segments will display improved motility on the echocardiogram after revascularization. The addition of ECG gating does not significantly increase the predictive value of SPET imaging with regard to recovery of function.