Re: [DIYbio] Father’s genetic quest pays off

I don't see any distinction here. He's doing genetic research mostly at
home for personal family reasons: to me, that epitomises the
empowerment of DIYbio. I've always considered his work a fantastic
go-to to illustrate why this stuff is important.

On Thu, 27 Jun 2013 09:54:57 -0400
Avery louie <inactive.e@gmail.com> wrote:

> Interesting, I haven't heard of this guy, so I am a bit concerned that
> nature is lumping him in with diybio. Im not offended or anything,
> but that sword can swing either way, depending on what the person.
>
> If you are on this list hugh, congrats. And if you havent heard of
> diybio before, welcome.
> On Jun 27, 2013 9:39 AM, "Eugen Leitl" <eugen@leitl.org> wrote:
>
> >
> > http://www.nature.com/news/father-s-genetic-quest-pays-off-1.13269
> >
> > Father's genetic quest pays off
> >
> > Mutation provides clue to daughter's undefined syndrome.
> >
> > Brendan Maher
> >
> > 26 June 2013
> >
> > Hugh Rienhoff prepared his daughter's DNA for sequencing at home
> > using second-hand equipment. LEAH FASTEN
> >
> > Hugh Rienhoff says that his nine-year-old daughter, Bea, is "a fire
> > cracker",
> > "a tomboy" and "a very sassy, impudent girl". But in a forthcoming
> > research paper, he uses rather different terms, describing her
> > hypertelorism (wide spacing between the eyes) and bifid uvula (a
> > cleft in the tissue that hangs from the back of the palate). Both
> > are probably features of a genetic syndrome that Rienhoff has
> > obsessed over since soon after Bea's birth in 2003. Unable to put
> > on much muscle mass, Bea wears braces on her skinny legs
> > to steady her on her curled feet. She is otherwise healthy, but
> > Rienhoff has
> > long worried that his daughter's condition might come with serious
> > heart problems.
> >
> > Rienhoff, a biotech entrepreneur in San Carlos, California, who had
> > trained as a clinical geneticist in the 1980s, went from doctor to
> > doctor looking for
> > a diagnosis. He bought lab equipment so that he could study his
> > daughter's DNA himself -- and in the process, he became a symbol
> > for the do-it-yourself biology movement, and a trailblazer in using
> > DNA technologies to diagnose a rare disease (see Nature 449,
> > 773-776; 2007).
> >
> > "Talk about personal genomics," says Gary Schroth, a research and
> > development
> > director at the genome-sequencing company Illumina in San Diego,
> > California,
> > who has helped Rienhoff in his search for clues. "It doesn't get
> > any more personal than trying to figure out what's wrong with your
> > own kid."
> >
> > Now nearly a decade into his quest, Rienhoff has arrived at an
> > answer. Through the partial-genome sequencing of his entire family,
> > he and a group of
> > collaborators have found a mutation in the gene that encodes
> > transforming growth factor-β3 (TGF-β3). Genes in the TGF-β pathway
> > control embryogenesis,
> > cell differentiation and cell death, and mutations in several
> > related genes have been associated with Marfan syndrome and
> > Loeys-Dietz syndrome, both of which have symptomatic overlap with
> > Bea's condition. The mutation, which has
> > not been connected to any disease before, seems to be responsible
> > for Bea's clinical features, according to a paper to be published
> > in the American Journal of Medical Genetics.
> >
> > Hal Dietz, a clinician at Johns Hopkins University School of
> > Medicine in Baltimore, Maryland, where Rienhoff trained as a
> > geneticist, isn't surprised
> > that the genetic culprit is in this pathway. "The overwhelming early
> > hypothesis was that this was related," says Dietz, who co-discovered
> > Loeys-Dietz syndrome in 2005.
> >
> > Rienhoff had long been tapping experts such as Dietz for
> > assistance. In 2005,
> > an examination at Johns Hopkins revealed Bea's bifid uvula. This
> > feature, combined with others, suggested Loeys-Dietz syndrome,
> > which is caused by mutations in TGF-β receptors. But physicians
> > found none of the known mutations after sequencing these genes
> > individually. This was a relief: Loeys-Dietz is associated with
> > devastating cardiovascular complications and an average life span
> > of 26 years.
> >
> > In 2008, Jay Flatley, chief executive of Illumina, offered Rienhoff
> > the chance to sequence Bea's transcriptome -- all of the RNA
> > expressed by a sample
> > of her cells -- along with those of her parents and her two
> > brothers. After drilling into the data, Rienhoff and his
> > collaborators found that Bea had inherited from each parent a
> > defective-looking copy of CPNE1, a poorly studied gene that seems
> > to encode a membrane protein. It looked like the answer.
> >
> > But questions remained. The gene did not have obvious connections
> > to Bea's features, and publicly available genome data suggests that
> > the CPNE1 mutations are present in about 1 in 1,000 people -- an
> > indication that there should be many more people like Bea.
> >
> > Unsatisfied, Rienhoff went back to Illumina in 2009 to ask for more
> > help. He
> > proposed exome sequencing, which captures the whole protein-encoding
> > portion
> > of the genome, and is in some ways more comprehensive than
> > transcriptome sequencing. At the time, Illumina was developing its
> > exome-sequencing technology, and the company again took on the
> > Rienhoff family as a test group.
> >
> > The analysis pulled up a mutation in one copy of the gene that
> > encodes TGF-β3
> > -- just in Bea. In cell culture and experiments in frog eggs, the
> > faulty gene
> > seems to produce a non-functional protein that reduces TGF-β
> > signalling. This
> > mechanism would differ from what many suspect is going on in Marfan
> > and Loeys-Dietz syndromes, in which mutations paradoxically amp up
> > TGF-β signalling. A collaborator of Rienhoff is now engineering a
> > mouse that shares
> > Bea's gene variant, which could help to clarify whether the
> > mutation revs up
> > signalling or suppresses it.
> >
> > The latest study does not define a new 'Rienhoff syndrome'. For
> > that, Rienhoff and his collaborators would need to find other
> > patients who share Bea's features and genetic markers. Rienhoff
> > says that he would be relieved if he found an older person with
> > similar symptoms who seems as vivacious as his daughter, who
> > recently earned an orange belt in karate; it would tell him
> > that cardiovascular complications are not pre-ordained. "If I saw a
> > single case, I might say, 'Hallelujah'," he says.
> >
> > Nature 498, 418-419 (27 June 2013) doi:10.1038/498418a
> >
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