[PAGID] FW: VOD/CID - Sp110

[Tony Roscioli]

Dear Jack, I agree with John's comments.  We had certainly wondered whether SP110 could be a susceptibility gene for VOD post HSCT and so made an attempt to identify at-risk alleles with a SNP association study.  Unfortunately, large well characterised cohorts of people with VOD post HSCT are not available.  The best we could do 2 years ago was about 240 people (through our collaboration with George MacDonald and Joanne Wang at the Fred Hutch in Seattle).  This study did not identify a signal in SP110 that stood up to multiple corrections.  Unfortunately, this study has not been able to be published (always difficult with negative results).  We are in the process of identifying a couple of thousand people with VODI post HSCT (once again through Seattle).  It is likely that as the methodologies for SNP association studies have improved, this will be a genome wide scan.  We all hypothesize that SP110 could have an effect in VOD post HSCT: the liver phenotype in VODI is so specific and also without genetic precedent that it is likely to be telling us something about the biology of VOD.  It could of course be one of the SP110 partners as well. We have not seen any hepatic phenotype is family members of people with VODI.  Perhaps not too surprising given that most autosomal recessive conditions do not have a phenotype in heterozygous form.   Equally, we have also looked for SP110 and SP140 gene mutations in children and adults with related immunodeficiencies and have found none.  It is plausible that additional mutations will be identified with time and that the phenotype may expand to related immunodeficiencies.  We would of course be interested to hear from you if you have any patients with overlapping phenotypes or with VODI.  We only know of one definite VODI case in the US but it is likely that there is also another family (not able to be confirmed as no DNA available). The other arm of this work is via expression microarrays in VODI patients.  These data will be published soon along with clinical information on newly ascertained children (another in Southern Italy with a further novel mutation).  I will keep you posted regarding this. It will also be presented at the PID meeting in Yokohama in December. best regards  Tony  Dr Tony Roscioli FRACP PhDClinical Geneticist, Sydney South West Area Health ServiceNHMRC post-doctoral research fellow, Nijmegen > Date: Sat, 27 Sep 2008 08:24:22 -0400> From: Jack.Bleesing at cchmc.org> To: pagid at list.clinimmsoc.org> CC: MelanieW at chw.edu.au; rosciolit at hotmail.com; Brynn.Wainstein at sesiahs.health.nsw.gov.au; michael.buckley at sesiahs.health.nsw.gov.au; simon.cliffe at sesiahs.health.nsw.gov.au> Subject: [SPAM?] Re: [PAGID] VOD/CID - Sp110> > Thanks John:> > I had been hoping for your input. Finishing the Sp110 inquiry, any reason to think that this gene is a susceptibility gene for VOD post HSCT?> > Have you considered other Sp family members. For example, Sp100 is a target autoantigen in autoimmunity affecting bile ducts (including primary biliary cirrhosis) and it's expression is affected by [viral] infections and other stimuli.> > Regards,> > Jack> > ---------------------------------------------------------------------------> Jack J.H. Bleesing, M.D., Ph.D.> Associate Professor of Pediatrics> Cincinnati Children's Hospital Medical Center> Division of Hematology/Oncology> 3333 Burnet Avenue, MLC 7015> Cincinnati, OH 45229> 513-636-4266 (phone)> 513-636-3549 (fax)> Jack.Bleesing at CCHMC.org> http://www.cincinnatichildrens.org/immunodeficiencies/> > > >>> "John B. Ziegler" <j.ziegler at unsw.edu.au> 9/27/2008 3:14 AM >>>> Jack> > In Sydney we have seen about 20 children with VODI often with large > sibships. Although only a minority of the siblings has been genotyped > we can speculate that there have been about 20 heterozygous siblings > as well as a similar number of carrier parents, about 40 people. > Among them there has been no phenotype. In addition there has been > genotyping carried out on some candidate phenotype cohorts, with no > heterozygotes identified.> > That said, it seems pretty clear to us that VODI cases in Lebanese > communities are probably going undetected. In the Sydney Lebanese > communities the carrier frequency appears to be about > 1:50. Extrapolating that to the population of Lebanon we would > expect 8 new cases a year in that country. And it could be expected > to be seen in other expatriate Lebanese communities. It has been seen > in both Muslim and Christian families and they don't appear to > originate in any particular part of Lebanon. Two sp110 mutations have > been detected in the Sydney cohort. (Other mutations have been seen > in non-Lebanese babies in the US and Italy.) HLH has not been seen > to date. The immunological phenotype does resemble CVID in that there > is usually marked hypogamma but no lymphopenia and standard T cell > function testing is usually normal. There has occasionally been a > SCID phenotype.> > That said, it is clearly early days and I'm sure we don't know the > full story about the clinical phenotype(s). Indeed the phenotype > paper lamentably langusihes as a manuscript. You can get more > information at > http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vodi.> > Your patients sound like an interesting group, rare presentation of > heterozygotes would have to be a possibility, or a milder phenotype > associated with mutations with less impact on the function of sp110 > than has been seen in VODI.> > Best wishes> > John> > . 10:40 PM 26/09/2008, you wrote:> >Good morning Folks:> >> >I was wondering if there is anybody, who would like speculate > >whether [mono-allelic] Sp110 mutations have a clinical phenotype.> >> >The reason I am asking is that every couple of months or so, we see > >a child (male and - seemingly healthy - present with severe > >hepatitis/cholangitis that is cellular based (no autoantibodies and > >no response to "low" dose steroids). When we get involved and look > >at the immune system (sometimes before steroids are started, as the > >Liver Team is starting to see a pattern as well), it looks like a > >SCID/CID immune system. Multi-gene workup of everything under the > >CID/HLH/XLP Sun, has not shown any defect.> >> >The cellular mechanism in the liver appears to suggest a HLH-like > >process (with increased sIL-2Ra and ferritin) with cytotoxic > >T-cells, akin EBV-driven HLH. In the liver, we sometimes, not > >always, find some virus (HHV-6, entervirus, adenovirus found so > >far), suggesting that a viral infection provided the trigger. When > >we initiate HLH therapy, things improve relatively quickly. > >Cytopenias, especially involving platelets and neutrophils are > >invariably present, sometimes with hemophagocytosis in the bone > >marrow. Coagulapathy (not due to synthetic dysfunction) also.> >> >Sp110 hasn't been looked at.> >> >Regards,> >> >Jack> >> >---------------------------------------------------------------------------> >Jack J.H. Bleesing, M.D., Ph.D.> >Associate Professor of Pediatrics> >Cincinnati Children's Hospital Medical Center> >Division of Hematology/Oncology> >3333 Burnet Avenue, MLC 7015> >Cincinnati, OH 45229> >513-636-4266 (phone)> >513-636-3549 (fax)> >Jack.Bleesing at CCHMC.org > >http://www.cincinnatichildrens.org/immunodeficiencies/ > > A/Prof John B. Ziegler> Department of Immunology and Infectious Diseases> Sydney Children's Hospital> High Street, RANDWICK NSW 2031> Australia> Tel: (02) 93821515> Fax: + 61 + 2 + 93821580> Email: j.ziegler at unsw.edu.au > > 

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