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1.  Urinary Neutrophil Gelatinase-Associated Lipocalin Predicts Mortality and Identifies Acute Kidney Injury in Cirrhosis 
Digestive diseases and sciences  2012;57(9):2362-2370.
Background
Kidney failure predicts mortality in patients with cirrhosis. Identification of kidney failure etiology and recognition of those at the highest mortality risk remains a challenge.
Aims
We hypothesized that urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) predicts mortality and identifies hepatorenal syndrome (HRS) in patients with cirrhosis.
Methods
Prospectively enrolled patients with cirrhosis were investigated by uNGAL immunoblot upon hospital admission. Kidney failure type was determined blinded to NGAL measurements.
Results
One hundred and eighteen patients were enrolled. Fifty-two (44%) patients had normal kidney function, 14 (12%) stable chronic kidney disease, 17 (14%) prerenal azotemia, 20 (17%) HRS, and 15 (13%) intrinsic acute kidney injury (iAKI). Patients with HRS had uNGAL levels intermediate between prerenal azotemia [median (IQR) 105 (27.5–387.5) v. 20 (15–45) ng/ml, p=0.004] and iAKI [325 (100–700), p<0.001]. Fifteen (13%) patients died. In unadjusted analysis, uNGAL predicted inpatient mortality (OR 2.00, 95% CI 1.36–2.94) and mortality or liver transplantation (OR 2.01, 95% CI 1.42–2.85). In multiple regression models, uNGAL>110 ng/ml (OR 6.05, 95% CI 1.35–27.2) and HRS (OR 6.71, 95% CI 1.76–25.5) independently predicted mortality, adjusting for age and serum creatinine>1.5 mg/dL.
Conclusions
uNGAL strongly predicts short term inpatient mortality in both unadjusted and adjusted models. Patients with HRS may have uNGAL levels intermediate between those with prerenal azotemia and iAKI. Further studies are needed to determine if uNGAL can improve discrimination of HRS from other types of acute kidney injury and predict short- and long-term cirrhosis outcomes.
doi:10.1007/s10620-012-2180-x
PMCID: PMC3979299  PMID: 22562534
Acute kidney injury; biomarker; cirrhosis; hepatorenal syndrome; NGAL; mortality
2.  No Evidence of Association between Common Autoimmunity STAT4 and IL23R Risk Polymorphisms and Non-Anterior Uveitis 
PLoS ONE  2013;8(11):e72892.
Objective
STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes.
Methods
Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain.
Results
No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15).
Conclusion
Our results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant.
doi:10.1371/journal.pone.0072892
PMCID: PMC3843656  PMID: 24312163
3.  Two Functional Variants of IRF5 Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis 
PLoS ONE  2013;8(10):e76777.
Objective
Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes.
Methods
Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin.
Results
A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (PFDR=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and PFDR=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients.
Conclusion
Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.
doi:10.1371/journal.pone.0076777
PMCID: PMC3792064  PMID: 24116155
4.  The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions 
Next generation exome sequencing (ES) and whole genome sequencing (WGS) are new powerful tools for discovering the gene(s) that underlie Mendelian disorders. To accelerate these discoveries, the National Institutes of Health has established three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Disorders at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and Johns Hopkins University. The CMGs will provide ES/WGS and extensive analysis expertise at no cost to collaborating investigators where the causal gene(s) for a Mendelian phenotype has yet to be uncovered. Over the next few years and in collaboration with the global human genetics community, the CMGs hope to facilitate the identification of the genes underlying a very large fraction of all Mendelian disorders see http://mendelian.org.
doi:10.1002/ajmg.a.35470
PMCID: PMC3702263  PMID: 22628075
mendelian; exome sequencing; commentary
5.  Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition 
BMC Medical Genetics  2013;14:52.
Background
Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition.
Methods
A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays.
Results
A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P-value=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci.
Conclusion
Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.
doi:10.1186/1471-2350-14-52
PMCID: PMC3658927  PMID: 23676143
Uveitis; IL2; IL21; IL2RA; IL2RB; Polymorphisms; Association study; Genetic susceptibility
6.  SynaptomeDB: an ontology-based knowledgebase for synaptic genes 
Bioinformatics  2012;28(6):897-899.
Motivation: The synapse is integral to the function of the brain and may be an important source of dysfunction underlying many neuropsychiatric disorders. Consequently, it is an excellent candidate for large-scale genomic and proteomic study. However, while the tools and databases available for the annotation of high-throughput DNA and protein are generally robust, a comprehensive resource dedicated to the integration of information about the synapse is lacking.
Results: We present an integrated database, called SynaptomeDB, to retrieve and annotate genes comprising the synaptome. These genes encode components of the synapse including neurotransmitters and their receptors, adhesion/cytoskeletal proteins, scaffold proteins, membrane transporters. SynaptomeDB integrates various and complex data sources for synaptic genes and proteins.
Availability: http://psychiatry.igm.jhmi.edu/SynaptomeDB/
Contact: mpirooz1@jhmi.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts040
PMCID: PMC3307115  PMID: 22285564
7.  Monomeric neutrophil gelatinase associated lipocalin is associated with tubulointerstitial damage in chronic kidney disease 
Kidney international  2012;82(6):718-722.
The rate of progression of chronic kidney disease (CKD) is difficult to predict using single measurements of serum creatinine or proteinuria. On the other hand, documented tubulointerstitial disease presages worsening CKD, but kidney biopsy is not practical for routine use and generally does not sample the tubulointerstitial compartment of the medulla. Perhaps a urine test that correlates with specific histological findings may serve as a surrogate for the kidney biopsy. Here we compared both immunoblot analysis (under non-reducing conditions) and a commercially available monomer immunoassays of Neutrophil Gelatinase Associated Lipocalin (NGAL) with pathological changes found in kidney biopsies, to determine whether specific histological characteristics associated with a specific NGAL species. We found that the urine of patients with advanced CKD contained NGAL monomers as well as higher molecular weight complexes containing NGAL, identified by MALDI-TOF/TOF mass spectroscopy. The NGAL monomer significantly correlated with glomerular filtration rate, interstitial fibrosis and tubular atrophy. Hence, specific assays of the NGAL monomer implicate histology associated with progressive, severe CKD.
doi:10.1038/ki.2012.195
PMCID: PMC3519389  PMID: 22695331
8.  Diagnostic and Prognostic Stratification in the Emergency Department Using Urinary Biomarkers of Nephron Damage 
Objectives
This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department.
Background
Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI.
Methods
In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase–associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization.
Results
All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events.
Conclusion
Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.
doi:10.1016/j.jacc.2011.10.854
PMCID: PMC3487165  PMID: 22240130
acute kidney injury; biomarkers; outcomes
9.  Simultaneous optic and vestibulocochlear syphilitic neuropathy in a patient with HIV infection 
Background
The purpose of this report is to present a case of optic and vestibulocochlear neuropathy as a manifestation of concurrent HIV and syphilis coinfection. This is an interventional case report of a 37-year-old man who complained of blurry central vision in his left eye and hearing loss in his left ear over the past 2 weeks.
Findings
Visual acuity was 20/20 in both eyes, and the anterior segment was normal in both eyes without relative afferent pupillary defect. Fundoscopy revealed swelling of the left optic disc. Optic coherence tomography and the Heidelberg retina tomograph confirmed and quantified the oedema of the left optic disc. An audiometry showed a left sensorineural deafness. Serological examinations disclosed confirmed HIV and syphilis infection. Magnetic resonance imaging of the brain showed no abnormalities. Properly treated with intravenous penicillin, the lesions resolved.
Conclusions
Simultaneous optic and auditive involvement can be the first manifestation of syphilitic and HIV coinfection. To our knowledge, this report is the first to describe the rare occurrence of syphilitic optic neuritis and ipsilateral affectation of the vestibulocochlear nerve.
doi:10.1186/1869-5760-3-27
PMCID: PMC3605106  PMID: 23514319
Hearing loss; HIV infection; Optic neuritis; Syphilis
10.  Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases 
Background
Collagen cross linking (CXL) of the cornea has been developed recently as a new treatment for multidrug-resistant infectious keratitis. The aim of this study is to summarize the previously published data and evaluate the effectiveness of this treatment.
Results
The search identified 12 articles. The number of eyes was 104. The infectious keratitis was associated with bacteria in 58 eyes (57f%): Gram-positive bacteria in 44 (43%; 4 of which were infected with Mycobacterium (3.6%)) and Gram-negative bacteria in 14 eyes (13%), fungus in 13 eyes (12%), and Acanthamoeba in 7 eyes (7%). In 26 eyes (25%), the microbiological culture was negative or not performed. The mean time of re-epithelization after CXL was 20.7±28.1 days (minimum of 3, maximum of 145). Sixteen eyes underwent deep or lamellar keratoplasty. The pooled analysis suggested that CXL has a favorable effect on the block of corneal melting in 85% (95%; CI 0.77, 0.91) of eyes.
Conclusion
Although randomized controlled trials are needed, the available evidence supports the use of CXL in the treatment of infectious keratitis.
doi:10.1186/1869-5760-3-47
PMCID: PMC3671959  PMID: 23718849
Collagen cross linking; Infectious keratitis; UV-A; Corneal melting
11.  Urine neutrophil gelatinase-associated lipocalin identifies unilateral and bilateral urinary tract obstruction 
Nephrology Dialysis Transplantation  2011;26(12):4132-4135.
Background. Urinary tract obstruction (UTO) is a common problem that can lead to permanent loss of kidney function. Unilateral UTO may be difficult to diagnose. Urinary neutrophil gelatinase-associated Lipocalin (uNGAL) may identify unilateral and bilateral UTO.
Methods. Retrospective case–control study of patients undergoing hospital admission at three sites. UTO was determined by review of medical records and cases were matched to control patients. uNGAL was measured by immunoblot.
Results. Twenty-four unilateral UTO and 15 bilateral UTO cases were identified. Admission serum creatinine (sCr) (milligram per decilitre) was significantly higher in bilateral UTO, 2.0 (1.1–5.3), but not unilateral UTO, 1.1 (0.8–1.5), compared to controls, 0.9 (0.8–1.2). uNGAL (nanogram per millilitre) was significantly higher both in patients with bilateral UTO, 140 (40–450), and unilateral UTO, 50 (20–100), compared to controls, 20 (10–45).
Discussion. uNGAL identifies kidney injury in unilateral and bilateral UTO even in the absence of an elevated sCr.
doi:10.1093/ndt/gfr569
PMCID: PMC3254163  PMID: 22049182
acute kidney injury; biomarkers; neutrophil gelatinase-associated lipocalin; obstructive nephropathy; urinary tract obstruction
12.  Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy 
Nephrology Dialysis Transplantation  2011;26(7):2387-2390.
Background. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD).
Methods. Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive.
Results. Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 μg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 μg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88.
Conclusion. In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.
doi:10.1093/ndt/gfr258
PMCID: PMC3164447  PMID: 21555394
biomarker; HIV-associated nephropathy; progressive chronic kidney disease; tubular injury; urinary neutrophil gelatinase-associated lipocalin
13.  Synthesis of the Cytotrienin A Core via Metal Catalyzed C-C Coupling 
Organic letters  2011;13(6):1482-1485.
A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, RCM delivers the cytotrienin core.
doi:10.1021/ol200160p
PMCID: PMC3075014  PMID: 21323372
14.  Neonatal Cholestasis as Initial Manifestation of Type 2 Gaucher Disease: A Continuum in the Spectrum of Early Onset Gaucher Disease 
JIMD Reports  2011;5:95-98.
Gaucher disease type 2 [OMIM #230800] is a rare lysosomal storage disorder with usual onset between 3 and 6 months of age leading to progressive neurodegeneration and death within the first 2 years of life. Rarely it may lack the characteristic symptom-free period and initially manifest prenatally or in the neonatal period. The early course of neonatal onset classic type 2 variants is not well known, and reports of early histological changes in the liver of type 2 Gaucher disease patients are scarce. We describe a patient who presented in the immediate postnatal period with cholestasis without hepatomegaly associated with hepatocellular giant-cell transformation on liver biopsy, thrombocytopenia, and failure to thrive. This was initially thought to represent neonatal giant-cell hepatitis and the correct diagnosis was not made until the age of 6 months. Hepatocellular giant transformation has not been described in the classic acute neuronopathic form of GD. However, it has been reported in congenital GD with nonimmune hydrops and neonatal hepatitis, an example of perinatal lethal Gaucher disease (PLGD), which sometimes is regarded as an entity separate from GD type 2. Our case illustrates that neonatal cholestasis may be part of a spectrum of manifestations which spans a continuum between the PLGD and classic type 2 GD. Giant cells are a nonspecific finding but may reflect the presence of a systemic inflammatory process that recently has been implicated in the brain stem degeneration associated with acute neuronopathic GD.
doi:10.1007/8904_2011_104
PMCID: PMC3509909  PMID: 23430923
15.  Replication of an association of a common variant in the Reelin gene (RELN) with schizophrenia in Ashkenazi Jewish women 
Psychiatric genetics  2010;20(4):184-186.
A single nucleotide polymorphism (rs7341475) in RELN has recently been shown to be associated with schizophrenia (SZ) in an Ashkenazi Jewish (AJ) case-control study specifically in women by Shifmen et al. We have replicated this association in women in another large independent AJ collection (721 cases, 259 female; 1455 controls, 834 female) and confirmed that it applies to both SZ and schizoaffective disorder. Further, we explore the effects of this polymorphism through quantitative trait loci (QTL) analysis of 9 SZ related factors providing information on sex-specific genotype-phenotype correlations.
doi:10.1097/YPG.0b013e32833a220b
PMCID: PMC2901865  PMID: 20431428
Schizophrenia; Reelin; Association; Endophenotype; Sex-specific; Ashkenazi; Jewish
16.  Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome 
Cell  2010;141(7):1171-1182.
Summary
Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further.
doi:10.1016/j.cell.2010.05.026
PMCID: PMC2943426  PMID: 20602999
17.  miRNA Mutations are Not a Common Cause of Deafness 
Mutations in miRNA genes have been implicated in hearing loss in human families and mice. It is also possible that mutations in miRNA binding sites of inner ear targets alter gene expression levels and lead to hearing loss. To investigate these possibilities we screened predicted target genes of the miR-183 miRNA family known to be expressed in the inner ear sensory epithelium. In one Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL), we identified a homozygous variant in a predicted miR-96/182 binding site in the 3′UTR of the RDX (DFNB24) gene. However, in vitro functional studies showed that this site is not a functional target for miR-96/182. We extended our study to include the miR-183 genes themselves and 24 additional predicted target genes of the miRNA-183 family. Screening these miRNAs and target sequences in numerous families segregating either autosomal dominant non-syndromic deafness (ADNSHL) or ARNSHL did not identify any potential deafness-causing mutations. These results suggest that mutations disrupting gene regulation by the miR-183 family are not a common cause of human hearing loss.
doi:10.1002/ajmg.a.33299
PMCID: PMC2830307  PMID: 20186779
radixin; ERM protein family; miRNA; ADNSHL; ARNSHL
18.  Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene 
PLoS Genetics  2010;6(6):e1000991.
Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders.
Author Summary
Metachondromatosis (MC) is an autosomal dominant condition characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests. MC exostoses may regress or even resolve over time, and short stature is not characteristic of MC. Here, we sequenced the whole genome of a single patient with MC and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which results in premature translation termination and co-segregates with the phenotype. In a second metachondromatosis family, we identified a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Germline gain-of-function missense mutations in PTPN11 cause an overlapping but distinct group of dominant disorders with involvement of the face, heart, skeleton, skin, and brain, including Noonan syndrome (OMIM 163950), Noonan-like disorder with multiple giant cell lesion syndrome (OMIM 163955), and LEOPARD syndrome (OMIM 151100). Nonsense mutations in PTPN11 have not been described in humans and the loss-of-function PTPN11 mutations we report here are the first to be described in human disease.
doi:10.1371/journal.pgen.1000991
PMCID: PMC2887469  PMID: 20577567
19.  1,n-Glycols as Dialdehyde Equivalents in Iridium Catalyzed Enantioselective Carbonyl Allylation from the Alcohol Oxidation Level and Iterative Two-Directional Assembly of 1,3-Polyols** 
doi:10.1002/anie.200901648
PMCID: PMC2843750  PMID: 19472247
Iridium; Allylation; Transfer Hydrogenation; Allyl Acetate; 1,3-Diol; Catalytic; Enantioselective
20.  Finding the missing heritability of complex diseases 
Nature  2009;461(7265):747-753.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
doi:10.1038/nature08494
PMCID: PMC2831613  PMID: 19812666
21.  Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes 
Amino acids  2008;35(4):655-664.
Proline metabolism in mammals involves two other amino acids, glutamate and ornithine, and five enzymatic activities, Δ1-pyrroline-5-carboxylate (P5C) reductase (P5CR), proline oxidase, P5C dehydrogenase, P5C synthase and ornithine-δ-aminotransferase (OAT). With the exception of OAT, which catalyzes a reversible reaction, the other 4 enzymes are unidirectional, suggesting that proline metabolism is purpose-driven, tightly regulated, and compartmentalized. In addition, this tri-amino-acid system also links with three other pivotal metabolic systems, namely the TCA cycle, urea cycle, and pentose phosphate pathway. Abnormalities in proline metabolism are relevant in several diseases: six monogenic inborn errors involving metabolism and/or transport of proline and its immediate metabolites have been described. Recent advances in the Human Genome Project, in silico database mining techniques, and research in dissecting the molecular basis of proline metabolism prompted us to utilize functional genomic approaches to analyze human genes which encode proline metabolic enzymes in the context of gene structure, regulation of gene expression, mRNA variants, protein isoforms, and single nucleotide polymorphisms.
doi:10.1007/s00726-008-0107-9
PMCID: PMC2707926  PMID: 18506409
Apoptosis; FASTSNP; Functional genomics; OAT; OH-POX; OMIM; P53; Δ1-pyrroline-5-carboxylate (P5C); P5CDH; P5CR/PYCR; P5CS/PYCS; POX/PRODH; L-Proline; Promoter analysis; SNP
23.  THE SPECIAL ISSUE “PROLINE METABOLISM IN HEALTH AND DISEASE” 
Amino acids  2008;35(4):651-652.
doi:10.1007/s00726-008-0102-1
PMCID: PMC2659409  PMID: 18504525
24.  PHR1, a PH Domain-Containing Protein Expressed in Primary Sensory Neurons 
Molecular and Cellular Biology  2004;24(20):9137-9151.
Previously, we identified PHR1 as an abundantly expressed gene in photoreceptors and showed that it encodes four isoforms, each with N-terminal pleckstrin homology (PH) and C-terminal transmembrane domains. To better understand PHR1 function and expression, we made a Phr1 null mouse by inserting a β-galactosidase/neor cassette into exon 3. In addition to photoreceptors, we found abundant expression of specific Phr1 splice forms in olfactory receptor neurons and vestibular and cochlear hair cells. We also found Phr1 expression in cells with a possible sensory function, including peripheral retinal ganglion cells, cochlear interdental cells, and neurons of the circumventricular organ. Despite this discrete expression in known and putative sensory neurons, mice lacking PHR1 do not have overt sensory deficits.
doi:10.1128/MCB.24.20.9137-9151.2004
PMCID: PMC517893  PMID: 15456885
25.  PEX11α Is Required for Peroxisome Proliferation in Response to 4-Phenylbutyrate but Is Dispensable for Peroxisome Proliferator-Activated Receptor Alpha-Mediated Peroxisome Proliferation 
Molecular and Cellular Biology  2002;22(23):8226-8240.
The PEX11 peroxisomal membrane proteins promote peroxisome division in multiple eukaryotes. As part of our effort to understand the molecular and physiological functions of PEX11 proteins, we disrupted the mouse PEX11α gene. Overexpression of PEX11α is sufficient to promote peroxisome division, and a class of chemicals known as peroxisome proliferating agents (PPAs) induce the expression of PEX11α and promote peroxisome division. These observations led to the hypothesis that PPAs induce peroxisome abundance by enhancing PEX11α expression. The phenotypes of PEX11α−/− mice indicate that this hypothesis remains valid for a novel class of PPAs that act independently of peroxisome proliferator-activated receptor alpha (PPARα) but is not valid for the classical PPAs that act as activators of PPARα. Furthermore, we find that PEX11α−/− mice have normal peroxisome abundance and that cells lacking both PEX11α and PEX11β, a second mammalian PEX11 gene, have no greater defect in peroxisome abundance than do cells lacking only PEX11β. Finally, we report the identification of a third mammalian PEX11 gene, PEX11γ, and show that it too encodes a peroxisomal protein.
doi:10.1128/MCB.22.23.8226-8240.2002
PMCID: PMC134051  PMID: 12417726

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