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EUROPEAN HUMAN GENETICS CONFERENCE 2010 REPORT
By Sabrina Carrella, Ph.D. Student
The EUROPEAN HUMAN GENETICS CONFERENCE in Gothenburg (Sweden, June 12-15, 2010)
examined several different topics: there were numerous opportunities to glean new information and to
learn about new devices and approaches to detect and treat different human genetic diseases. In
particular, one of the most interesting arguments concerned the massive potential of technologies such
as next generation sequencing to identify the genetic basis of rare disorders using samples from only a
handful of patients.
Society President Dian Donnai believes that the during last 10 years there has been considerable
progress and the changes have been enormous. She said that the next generation sequencing technology
will provide many more discoveries that will help us to understand the predisposition to complex
diseases and the biological pathways involved in disease.
"Patients have to be prepared for genetic testing and genetic-based therapy, and there is a big deficit in
the genetic knowledge of doctors and nurses in, perhaps, the majority of European countries", she said.
"We need to address things like the educational needs of medical and nursing training, but also to
involve the public more in what's going on in genetics.
This is a big challenge, and it's important to find the right way to do it."
Professor Sir Alec Jeffreys FRS (Royal Society Wolfson Research professor in the Department of
Genetics at the University of Leicester, England, UK) argued that these technologies are not going to
be the answer to everything and that a new approach is needed.
He said: "To go further we need to start off with whole genome sequences on very large cohorts of
people and couple this with a lot of bioinformatics linking with information about tissue-specific
expression profiling, epigenetic, epigenome scans, etc..”.
Attending the different oral presentations given at the congress it was possible to observe how useful
these new technologies can be in different fields of human genetic research.
The Scientific Programme Committee analyzed the 1718 abstracts submitted and selected a group of
abstracts for the oral presentations that could give us the opportunity to gain interesting information on
different aspects of all the topics examined during the congress. This series of reports is based on some
of the presentations by scientists and scientist/clinicians at the ESHG congress.
On the first day, June 12th 2010, during the Opening Plenary Session 1, there was the first example of
how the new technologies can have an impact on our lives and patients’ lives.
• Genetics of cancer predisposition
(L. A. Aaltonen)
Many of the early molecular studies on cancer predisposition focused on large pedigrees segregating
syndromic cancer susceptibility phenotypes.
The advances of the human genome project have brought in new resources year after year, such as
better genetic markers and maps, and finally the full human genomic sequence and the technologies to
analyze it at an acceptable cost.
The speaker focused the attention on the latest developments that have led to the unraveling of the
underlying genetic components of most high penetrance cancer syndromes. In fact, genome wide
association studies have taken the work forward, towards population level cancer susceptibility.
However, such disease phenotypes have been resistant to research by traditional methods such as
linkage and top GWAS approaches.
The speaker stated that next generation sequencing will unravel this key component of the genetics of
cancer predisposition in the near future and concluded saying that this task will require considerable
effort from the many health care professionals dealing with these issues.
Particularly exciting new findings were presented in a “what’s new?” session:
• The Effect of Translocation-Induced Nuclear Re-organization on Gene Expression
(L. Harewood)
Translocations are known to affect the expression of genes at the breakpoints and, in the case of
unbalanced translocations, to alter the gene copy number.
Dr. Louise Harewood showed us her work in which she has studied the effect of balanced
chromosomal rearrangements on gene expression by comparing transcriptomes of cell lines from
controls and individuals with the t (11; 22) (q23; q11) translocation. The number of differentially
expressed transcripts between translocation carrying and control cohorts was significantly higher than
that observed between control samples alone, suggesting that balanced rearrangements have a greater
effect on gene expression than normal variations. Many of the affected genes are located on the
derivative chromosome 11. They show that this chromosome is concomitantly altered in its spatial
organization, occupying a more central position in the nucleus than its non-rearranged counterpart.
She said that their results are consistent with recent studies that indicate that nuclear position plays a
functional role in regulating the expression of some genes. Their study suggests that chromosomal
translocations can result in large-scale changes in gene expression that are the consequence of
alterations in normal chromosome territory positioning.
• PDZD7 is a modifier of and digenic contributor to retinal disease in Usher syndrome
(H. J. Bolz)
Usher syndrome (USH), an inherited condition involving both hearing loss and retinitis pigmentosa
(RP), is not simply a recessively inherited disease; in fact there is often an unexplained variability of
the visual characteristics of the condition, even between close family members. Dr. Hanno Bolz
(Associate Medical Director of the Bioscientia Centre for Human Genetics, Ingelheim, Germany, and
active in teaching and research at the University Hospital of Cologne) said that his team’s research
challenges the traditional view that USH was inherited as a single gene disorder, and showed that it
may result from at least two different genetic mutations.
Using a genome-wide database search they identified PDZD7, encoding a homolog of proteins mutated
in Usher subtypes 1C and 2D (USH1C, USH2D). They demonstrated the interaction between PDZD7
and two Usher disease proteins, GPR98 (USH2C) and USH2A, and their colocalization in the
photoreceptor’s connecting cilium region. Moreover on a homozygous USH2A mutation background,
they showed that PDZD7 aggravates RP.
In this work they were able to validate these findings in transgenic zebrafish, because visual defects are
typically not evident in mouse models of Usher syndrome, and to show that PDZD7 localizes to the
cilia, thus providing further confirmation that USH is a retinal ciliopathy.
Their data in zebrafish were consistent with the digenic inheritance of PDZD7 and GPR98, and with
PDZD7 as a retinal disease modifier in USH2A patients. Pdzd7 knockdown produced an Usher-like
phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and
significantly reduced Gpr98 localization in the region of the photoreceptor connecting cilium.
Dr. Bolz said “With advances in new sequencing techniques that permit simultaneous analysis of
several genes, we will need to interpret variants in all Usher genes in a patient, not only in one. Two
hits in a single Usher gene may explain the disease in one patient, but not its variability. Our research is
a step on the road to understanding that variability and to being able to provide an accurate prognosis of
disease progression”. This could lead to a more accurate diagnosis of this condition, which is
responsible for up to 10% of all cases of childhood deafness and 50% of all deafness/blindness in
adults.
• De novo mutations of SETBP1 cause Schinzel-Giedion syndrome
(Hoischen,B)
Schinzel-Giedion syndrome is characterized by severe mental retardation and characteristic facial
features. Most patients die before the age of 10 years.
The exomes of four affected individuals with Schinzel-Giedion syndrome were sequenced to a mean
coverage of 43-fold. On average 21,800 genetic variants were identified per patient. After filtering
against known variants and selecting variants affecting the same gene in all patients, only a single
candidate gene remained, SETBP1 which encodes SET binding protein 1.
Sequencing confirmed the presence of SETBP1 mutations in these 4 individuals as well as in 8
additional Schinzel-Giedion syndrome patients. All mutations occurred de novo and all mutations were
missense, and clustered to an ultra highly conserved 11bp exonic region of SETBP1. In conclusion,
their study shows the potential of exome sequencing for disease gene identification by unraveling the
first dominant Mendelian disorder. Exome sequencing is particularly useful for identifying these types
of mutations for which no other genome wide approach is applicable.
•
Complete genome sequencing and analysis of diploid African-American and MexicanAmerican genomes: implications for personal ancestry reconstruction and multi-ethnic
medical genomics
(F. M. De La Vega)
Understanding the genetic ancestry of mixed populations, such as those found in North America, can
not only help to detect their origins but also to understand the genetic basis of complex diseases. “It is
the first time that the genomes of individuals of admixed ancestry have been sequenced in such detail”,
said Dr. Francisco De La Vega (Life Technologies, Foster City, California, USA).
At the congress he presented results from the sequencing, assembly, and genomic analysis of two
genomes using the SOLiD System, a greatly increasing the resolution of the analyses and achieving a
very much clearer picture of the ancestry of genome sequences for the individuals studied.
The donor individuals were of Mexican and African ancestry and represented the first "admixed"
genomes to be sequenced to high coverage. They demonstrated that genomic sequencing provides a
finer resolution of "admixture breakpoints" based on allele frequency estimates from HapMap and the
1000 Genomes Project. Finally, using the SOLiD comparative personal genomic data sets and 1000
Genomes data they quantified the relative proportions of private, rare, and common functional and
neutral genetic variations. “We believe that our work will help move forward genetic disease
association studies in these admixed populations”, said Dr. De La Vega, and he concluded “the
decreasing costs of sequencing genomes through new sequencing instruments such as those developed
by Life Technologies, is making it possible for the first time to compare on a large scale genetic
variants among and within populations”.
•
A mutation in the 3'UTR of the HDAC6 gene abolishing the post-transcriptional
regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked
chondrodysplasia
(B. Arveiler)
A family with dominant X-linked chondrodysplasia had previously beendescribed. The disease locus
was ascribed to a 24 Mb interval in Xp11.3-q13.1. The speaker presented the data in which they have
identified a variant *281A>T in the 3’UTR of the HDAC6 gene that totally segregates with the disease.
The variant is located in the seed sequence of hsa-miR-433. They demonstrated that hsa-miR-433
(miR433) down-regulated both the expression of endogenous HDAC6 and that of an eGFP-reporter
mRNA bearing the wild-type 3’UTR of HDAC6. This effect was totally abrogated when the reporter
mRNA presents the mutated HDAC6 3’UTR. The HDAC6 protein was found to be over-expressed in
the thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of
HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alphatubulin was found to be profoundly decreased. These results strongly suggest that this HDAC6 3’UTR
variant suppressed the hsa-miR-433-mediated post-transcriptional regulation causing the over
expression of HDAC6. This variant is likely to constitute the molecular cause of this new form of Xlinked chondrodysplasia. In fact their working hypothesis is that this over expression can lead to
RUNX over expression and to IHH expression repression, which finally result in chondrogenesis
abnormality. This represents the first example of a skeletal disease caused by the loss of a miRNAmediated post-transcriptional regulation on its target mRNA, even if he specified that more experiment
will be performed to demonstrate their hypothesis using different animal model systems ( Danio rerio,
Xenopus laevis..).
On the second day, June 13th 2010, I presented our work titled “The microRNA miR-204 is required for
vertebrate eye development” during the Concurrent Sessions C04: Sensory Disorders and
Neurobiology.
• Identification of novel deafness genes by homozygosity mapping in Dutch families
(H. Kremer)
Novel autosomal recessive nonsyndromic hearing loss (arNSHI) loci are generally determined in large
consanguineous families and are often large (10-30 Mb).
In this work the authors followed a strategy of homozygosity mapping with high density SNP arrays in
125 patients with putative arNSHI from 77 families to delimit the critical region of known deafness loci
and/or identify novel loci. They identified two different regions and performed mutation analysis of all
the exons in these regions revealing putatively pathogenic mutations in GRXCR1 and PTPRQ.
Vestibular dysfunction can be associated with hearing loss for both genes.
• Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by
mutation in C20orf54
(D. J. Josifova)
Brown-Vialetto-Van Laere syndrome is a rare neurological disorder characterized by amyotrophic
lateral sclerosis with onset in infancy. The disease usually presents with VII, IX, X, XI and XII cranial
nerve palsies, which develop in a previously healthy individual. A complex neurological phenotype
evolves with disease progression. The course is invariably progressive, but the rate of decline is
variable within and between families. Here this group identified a candidate gene, C20orf54 by
studying a consanguineous family with multiple affected individuals and subsequently demonstrated
that mutations in this gene were the cause of disease in other, unrelated families.
• Phenotypic modifiers of DJ1
(S. Jain)
Parkinson’s disease (PD) is a slow progressing neurodegenerative disease with devastating clinical
symptoms. The authors conducted a high content screening for interactors of DJ1, a gene mutated in
PD to determine if any of them is capable of affecting DJ1 function. They have been able to identify
several genes which are able to rescue DJ1 deficits in cell viability such as PPP2R2C, PSF, 4E-BP and
other genes which are able to enhance the loss of DJ1.
4E-BP is a translational inhibitor for which many drugs are available. Therefore the administration of
4E-BP activators, such as rapamycin, may protect cells from apoptosis and thus may be an effective
treatment to prevent or delay the onset of the disease. Using this approach they have been able to
construct a detailed molecular pathway of the proteins that are involved in the function of DJ1 and to
identify additional therapeutic targets.
• MiR-135b regulates two transcriptional cofactors, PC4 and Psip1, in the mammalian
inner ear, identified using an integrative transcriptomic and proteomic approach
(K. B. Avraham)
The relevance of micro-RNAs to the inner ear has recently been emphasized by the discovery of
miRNA mutations leading to deafness in humans and mice. In this work the authors integrated a
comparative transcriptomic and proteomic analysis and a miRNA screen of early post-natal cochlear
and vestibular sensory epithelia derived from mice, with sequence-based predictions, to efficiently
identify functional miRNAs and their targets. Using FAME, a bioinformatic tool developed by Ron
Shamir, they identified PC4 and Psip1, two transcriptional cofactors that interact with one another, as
targets for miR-135b in the inner ear hair cells. PC4 mediates functional interactions between upstream
activators and general transcriptional machinery. Psip1 is involved in the transcriptional regulation of
stress related genes, mRNA splicing, and cell survival. In order to prove the interaction between the
miRNA and its target proteins, the miRNA was silenced or over-expressed in the cell line and the
protein levels were studied using semi-quantitative western blot analysis. Their attention focuses on
miR-135b regulation and its effects on downstream pathways in the inner ear.
• Olfactory Expression of Mutant A30P alpha-Synuclein in Conditional Mouse Brain:
Implications for Early Stage of Parkinson’s Disease
(S. Nuber)
Cognitive and psychiatric deficits precede motor impairment in Parkinson’s disease (PD). In this
premotor stage the neuropathology is detectable in the olfactory bulb and a smell deficiency is found in
about 90% of PD patients.
A fast, simple and non invasive test of the ability to smell may be an important tool to screen people
who are likely to develop Parkinson’s disease (PD), in which motor symptoms only become evident at
a later stage of the disease.
Dr. Silke Nuber, from the Department of Medical Genetics, University of Tübingen, Germany, said
that her team’s research could help in the development of treatments for the early stages of the disease.
They have generated and characterized a tet-off conditional mouse model expressing human [A30P]
alpha-synuclein in the olfactory bulb. Alpha-synuclein can be turned off in these animals by the
administration of an antibiotic, allowing scientists to look at the reversibility of the neuropathological
alterations. “The mice expressed alpha-synuclein primarily in the neurons of the olfactory bulb”, said
Dr. Nuber, “and we therefore expected to find alterations in smell-related behaviour in these
animals. Since one of the earliest symptoms in PD patients is a reduction in the sense of smell, we felt
that these mice could mimic the early stages of the disease.”
They found that over expressing the mutated [A30P] alpha-synuclein led to a down regulation of
dopamine neurotransmission in the olfactory bulb. In this way they have developed one of the first
models to show this olfactory dopamine deficit without additional abnormalities in the nigrostriatal
pathway. They have further detected an up regulation of neurotransmitter content in the striatum and
substantia nigra and mitochondrial dysfunction in the non-olfactory brain regions, both of which could
be reversed in old-aged mice. Using this transgenic mouse model, it is possible to model and explore in
detail the impact of olfactory alpha-synucleinopathy on other brain regions; this model is also a useful
tool to study early intervention strategies, which may halt or even reverse the massive dopaminergic
neurodegeneration that takes place in human PD patients.
Session S06 - Long Distance Regulation
• Disruption of long-distance highly conserved non coding sequences at the SOX9 locus
(S. Lyonnet)
Two thirds of non-coding elements that have remained evolutionarily conserved, named conserved
non-coding sequences (CNCs) do not correspond to transcribed sequences. Enrichment for CNCs has
been demonstrated within gene deserts nearest to physically isolated genes known or suspected to be
important developmental regulators. It has been suggested that in these cases CNCs may represent
regulatory elements (enhancers or suppressors) necessary for the correct spatiotemporal expression of
these genes needed for vertebrate development.
Here the speaker discussed recent findings from his group:
- A common non-coding enhancer genomic variant in a highly conserved sequence located in a noncoding region of the RET gene
- The discovery of a long-distance disruption of enhancer CNCs on both sides of the SOX9 gene
coding sequences in Pierre Robin sequence (PRS), a common orofacial cleft anomaly with mandibular
hypoplasia. Their data, combined with existing evidence from human and animal phenotypes, strongly
suggests that the disruption of distant, tissue-specific regulatory elements, required for the normal
development of the mandibula, perturbs the embryonic expression of SOX9 and accounts for the PRS
phenotype.
From these and other data that he showed us during his presentation, we gained information about the
genomic alteration of highly conserved non-coding elements, located near to, or at a long distance
from, the coding sequences of a gene that might alter gene expression in a tissue-specific and timespecific manner.
• Clustered gene co-regulation and enhancer sharing can be modulated by developmentally
regulated chromatin loops
(J. L. Gomez-Skarmeta)
The authors presented a general map of enhancer distribution in the IrxA and IrxB clusters analyzed
using transgenic Xenopus, zebrafish and mouse embryos. Using Chromatin Conformation Capture, they
demonstrated that enhancer sharing is widespread within the cluster, which explains the common
expression domains of IrxA genes in particular tissues and the evolutionarily conserved architecture of
the cluster. They also identified an insulator and two chromatin loops within the cluster that may help
partition it in two independent regulatory domains in certain cell types.
The speaker also showed us different examples of cluster gene regulation (e.g. six6-six1-six4),
suggesting the presence of developmentally regulated loops that facilitate the formation of genespecific regulatory landscapes for the clustered genes.
• Far reaching consequences - mechanisms and problems of long range control
(S. Mundlos)
Conserved non-coding elements (CNEs) are particularly abundant in “gene deserts” surrounding genes
that have important functions during development and may be as far as 1 Mb away from the gene they
regulate. The binding of transcription factors to the element and the subsequent loop formation between
the CNE and the gene’s promoter leads to the gene regulation. Mutations that interfere with the cis
regulatory capacity of these elements can thus be expected to result in an altered gene expression in a
certain cell type at a given time point. The speaker showed us their work in which they investigated the
consequences of CNE-controlled gene regulation and the effect of mutations using cytogenetic and
high-resolution array CGH in mouse models and patients.
They identified several molecular mechanisms that cause abnormalities in long range control. All
abnormalities were detected in patients or mice with congenital malformations. These include the
disconnection of control elements from their target gene by translocations, changes in presumed
transcription factor binding sites by point mutations, and altered gene regulation by deletions, and
duplications of CNEs. These data suggest that the congenital malformations are caused by alterations
of the fine tuning of gene expression which in consequence disturbs dosage-dependent signaling
pathways.
14 June 2010: Concurrent Session C09 – Mouse Genetics and Therapy
•
Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated to an up
regulation of the mTOR pathway
(D. Iaconis)
The Oral-Facial-Digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited
renal cystic disease caused by mutations in the OFD1 gene. Dr. Iaconis and her colleagues generated a
conditional inactivation of the mouse Ofd1 gene using the Ksp-cre transgenic line, which resulted in a
viable model characterized by renal cystic disease and a progressive impairment of renal function.
Studying this model they demonstrated that primary cilia initially form and then disappear after the
development of cysts, suggesting that the dysfunction of primary cilia is a consequence of renal cystic
disease. They demonstrated an upregulation of the mTOR pathway in the renal structures and that
treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction
in the number and size of the renal cysts and a decrease in the cystic index compared with untreated
mutant animals, suggesting that dysregulation of this pathway in the model is mTOR-dependent. This
animal model could allow the understanding of the molecular link between mTOR and cyst
development, and eventually the identification of novel drug targets for renal cystic disease.
•
Lack of Mid1, the mouse ortholog of the Opitz Syndrome gene, causes abnormal
development of the anterior cerebellar vermis.
(G. Meroni)
The X-linked form of Opitz G/BBB Syndrome (OS) is a genetic disorder characterized by midline
developmental defects caused by loss-of-function mutations in the MID1 gene. MID1 encodes an
ubiquitin ligase that controls Phosphatase 2A but its role in the pathogenesis of the disease is still
unclear.
Mid1 null mice show the brain anatomical defect observed in patients, i.e. hypoplasia of the anterior
portion of the medial cerebellum, the vermis. The authors showed that lack of Mid1 causes the
shortening of the posterior dorsal midbrain; the rostralization of the midbrain/cerebellum boundary; and
the down-regulation of Fgf17, a key player in the development of this region. Thus, lack of Mid1
causes a mis-specification of the midbrain/cerebellar boundary that results in an abnormal development
of the most anterior cerebellar lobes. For these reasons this animal model provides a tool for further in
vivo studies of the physiological and pathological role of the Mid1 gene.
•
The forkhead transcription factor FOXL2 is sumoylated in both human and mouse:
Sumoylation affects its stability, localization, and activity
(M. Marongiu)
Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome (BPES) is caused by mutations in the
FOXL2 forkhead transcription factor.
Inactivation of Foxl2 in mice demonstrated its indispensability for female gonad sex determination and
ovary development and revealed its antagonism of Sox9, the effector of male testis development.
In this work the authors looked for FOXL2 interacting proteins and using yeast-two-hybrid screening,
they found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery.
They confirmed the interactions by co-immunoprecipitation and demonstrated that human FOXL2 is
sumoylated in both in vitro and in vivo systems. They demonstrated that FOXL2 co-localizes with
SUMO-1, identified 7 putative sumoylation sites (using Abgent SUMOplot™software) and created
FOXL2 mutants in which the lysines (higher score putative sumoylation sites: K25, K87, K114, K150)
were changed to arginine. Their results indicate that K114 and K150 are involved in FOXL2
sumoylation, and nuclear localization and that all mutations influence FOXL2 transcriptional activity.
• SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy
(B. Wirth)
SMA is a common autosomal recessively inherited neuromuscular disorder determined by a functional
impairment of the α-motor neurons within the spinal cord. SMA is caused by a functional loss of the
survival motor neuron gene 1 (SMN1), whereas the disease severity is mainly influenced by the
number of SMN2 copies.
The authors analyzed two severe SMA mouse models each carrying two SMN2 transgenes and showed
that treatment with 25 mg/kg/2x/day SAHA increased the lifespan of SMA mice by 30%, significantly
improved motor function abilities, reduced degeneration of the motor neurons within the spinal cord
and increased the size of the neuromuscular junctions and muscle fibers compared to vehicle-treated
SMA mice. For these reasons SAHA might be suitable for SMA therapy.
Session S11 - RNA Molecules: Nature, Expression and Sense
• Mechanisms of miRNA-mediated gene silencing
(E.Izaurralde)
MicroRNAs (miRNAs) are able to silence gene expression post-transcriptionally and to exert their
function they associate with Argonaute proteins (AGOs) in miRNA-induced silencing complexes
(miRISCs). The AGO proteins are not sufficient to mediate silencing and require interaction with
proteins of the GW182 family. The speaker showed with different examples that AGO-GW182
complexes mediate silencing by promoting translational repression and mRNA deadenylation catalyzed
by CAF1-CCR4-NOT, the major cytoplasmic deadenylase complex. Deadenylation decreases
translation efficiency and commits the mRNA to decapping and 5’-to-3’ exonucleolytic degradation.
Using a new strategy (with a reporter gene that carries 5 BoxB) they analyzed GW182 protein function
in an independent way from the AGO protein function, and identified two domains critical for
silencing: an N-terminal GW-repeat-containing region conferring binding to the AGOs, and a bipartite
silencing domain, consisting of Mid and C-terminal regions, which elicits the translational repression
and degradation of miRNA targets. This domain interacts with the cytoplasmic poly (A)-binding
protein 1 (PABPC1) that is needed for the mRNA stability. This suggests that GW182 proteins are
PABP-interacting proteins (Paips) that interfere with the function of PABPC1 in mRNA stabilization
and translation.
•
The hidden layer of noncoding RNA in the epigenetic control of human development and
cognition
(J.S.Mattick)
The extent of non-protein-coding DNA increases with increasing complexity, reaching 98.8% in
humans, suggesting that much of the information required for programming development may reside in
these sequences. Moreover it is now evident that the majority of the mammalian genome is transcribed
into non-protein-coding RNAs (ncRNAs), and that there are a lot of long and short RNAs in mammals
that show specific expression patterns and subcellular locations. These studies indicate that these RNAs
form a massive network of regulatory information that regulates different processes and directs a
precise pattern of gene expression during growth and development. It also appears that RNAs are
important for brain development, learning and memory, and that primates have developed sophisticated
RNA editing systems to modify hardwired genetic information in response to experience, that in turn
can modulate epigenetic memory, some of which may be inherited. RNAs may hold the key to
understanding human evolution, development and cognition, as well as our individual differences and
susceptibilities to complex diseases.
• System genetics of non-coding RNA
(L. Steinmetz)
By profiling genome-wide transcription at a high resolution of the complete yeast genome, the speaker
and collaborators have found hundreds of novel intergenic and antisense non-coding RNA transcripts.
By comparing transcriptome profiles across multiple conditions and strains, they have defined an
annotated set of differentially expressed non-coding transcripts. Hundreds of non-coding RNAs appear
to arise from an inherent bi-directional transcription from eukaryotic promoters. Many others originate
from 3’ nucleosome depleted regions of genes and are transcribed antisense to the open reading frame.
The regulatory patterns of these transcripts suggest the mechanisms by which they could be regulated
and by which they could regulate the expression of other genes.
15 June 2010: Session S15 – Molecular Processes in Neurodegenerative Diseases
• Using Simple Cells to Model Complex Diseases
(S.L.Lindquist)
A surprising number of human diseases, especially neurodegenerative diseases, result from basic
problems in protein folding. One feature these diseases share is the occurrence of complexes of
misfolded, aggregated proteins in the affected neurons. In this work Dr. Lindquist and collaborators,
have developed simple cellular models of these protein folding disorders by over-expressing human
disease-associated proteins in yeast. They presented models for the misfolding of α-syn and Aβ using
yeast cells as “living test tubes” to investigate the mechanisms of toxicity associated with problems in
protein folding, trafficking, and degradation and complemented these basic studies with a
transcriptional analysis and high-throughput chemical and genetic screens for toxicity modifiers.
• C. elegans models for neurodegenerative diseases
(E. Nollen)
Some neurodegenerative diseases are associated with the accumulation of misfolded proteins in
aggregates in the brain.
Using the nematode worm Caenorhabditis elegans to model these diseases and high-throughput genetic
screens, Dr. Nollen and her group have identified genes that modify aggregation of the disease proteins
and their toxicity. They have recently identified an evolutionarily highly conserved (52% of similarity
with SERF-2) modifier of aggregation, moag-4, as a positive regulator of aggregate formation in C.
elegans models for misfolding diseases. They have shown, using mutants carrying the moag-4 deletion,
that this gene drives the formation of compact misfolding intermediates that are required for aggregate
formation and that a loss of moag-4 promotes longevity in parallel to the core IGF/insulin (IIS)
longevity pathway. Thus, moag-4 has a dual function as a regulator of protein aggregation and of
lifespan in C. elegans.
• The prion-like aspect of Alzheimer´s disease
(M.Jucker)
To understand the mechanisms by which abnormal protein processing and aggregation leads to cerebral
amyloidosis, cellular dysfunction, and dementia, several transgenic mouse models have been generated.
These mouse models have been instrumental in the study of the induction and spread of the
Alzheimer’s Disease (AD) lesions and a mechanism reminescent of prions has been suggested. The
observation that Aβ structural variants can be induced in vivo in these mouse models intensifies the
search for the agent that drives the corruptive protein templating in AD pathogenesis. AD lesions and
neurodegeneration likely occur many years before the clinical signs of the disease. Jucker's work could
lead to the identification of amyloid-inducing factors as pre-synthomatic tools for a diagnosis and early
mechanism-based intervention.
Concurrent Session C14 – Mutation Mechanism
•
Mutation in SHOC2 promotes aberrant protein N-myristoylation and underlies Noonanlike syndrome with loose anagen hair
(V. Cordeddu)
In this work the authors showed that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich
repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically
distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with
Noonan-like syndrome shared the 4A>G missense change (Ser2Gly) in SHOC2 that introduces an Nmyristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired
translocation to the nucleus upon growth factor stimulation. Induction of SHOC2S2G in
Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated
with aberrant signaling, suggesting that, as already demonstrated in vitro, this mutation enhanced
MAPK activation. These results document the first example of an acquired N-terminal lipid
modification of a protein causing human disease.
•
Another gene for autosomal recessive ALX-related frontonasal dysplasias: Disruption in
ALX1 (CART1) causes anophthalmia and severe facial clefting
(E. Uz)
The authors presented a new autosomal recessive frontonasal dysplasia in two families characterized by
bilateral anophthalmia/microphthalmia, a bilateral oblique facial cleft, a complete cleft palate,
hypertelorism, a wide nasal bridge and low set and posteriorly rotated ears. Using Affymetrix SNP
Array genotyping and homozygosity mapping, they mapped this clinical entity to chromosome 12q21.
In one of the families with three affected individuals, they detected a homozygous 3.7 Mb deletion
containing the ALX1 (aristales-related homeobox transcription factor 1 or CART1) gene. In the second
family, they identified a homozygous donor splice site mutation (c.537+1 G>A), which is predicted to
disrupt the functionally essential homeodomain structure of the ALX1 protein. These results provide
evidence that loss of ALX1 function causes a severe impairment of early craniofacial development.
This study further expands the spectrum of the recently recognized autosomal recessive “ALX-related
FND” phenotypes in humans.
Before the conclusion of the congress there was the prize giving of the ESHG awards for outstanding
research by young scientists presented as a spoken contribution at the conference. Additionally
Professor Sir. Alec Jeffreys was awarded with the ESHG Lecture AWARD speaking in Plenary
Session 5.
2010 Winners
Young Investigator Awards for Outstanding Science
Louise
The Effect of Translocation-Induced Nuclear Re-organization on Gene
Harewood
Expression
(Lausanne)
Silke
Nuber Expression of Mutant A30P alpha-Synuclein in Conditional Mouse Brain:
(Tübingen)
Implications for Early Stage of Parkinson's Disease
Sabrina Carrella The microRNA miR-204 is required for vertebrate eye development
(Naples)
Olli Pietiläinen Inverse mapping approach implies the role of large CNVs in intellectual
(Helsinki)
deficits
and
learning
difficulties
in
a
population
cohort
Shushant
Jain Phenotypic modifiers of DJ1
(Amsterdam)
Isabelle Oberlé Award
Suleyman
Targeted next generation sequencing identifies a mutation associated with
Gulsuner
cerebellar hypoplasia and mental retardation with quadrupedal locomotion
(Ankara)
Lodewijk Sandkuijl Award
Gosia
Trynka Multiple common genetic variants for coeliac disease influencing immune
(Groningen)
gene expression
Session: C03 Complex Diseases
ESHG Poster Awards
Emma
Burkitt SHOC2 mutations in patients with cardio-facio-cutaneous syndrome
Wright
P02.036
(Manchester)
Alev Erogullari A functional link of DYT1 and DYT6 dystonia: Repression of TOR1A
(Lükeck)
(DYT1) gene expression by the transcription factor activity of THAP1
(DYT6)
PL5.1 - ESHG Award Lecture
• DNA fingerprinting and the turbulent genome
(Jeffreys)
University of Leicester, Department of Genetics, Leicester, United Kingdom.
Sir. A. Jeffreys discussed the origins and evolution of DNA testing, the creation of major national DNA
databases and the extraordinary impact that DNA has had on forensic and legal medicine. The
presentation also focused the attention on how DNA fingerprinting has identified some of the most
unstable regions in the human genome, allowing us to study human DNA evolution in real time and to
explore the fundamental processes of mutation and recombination that are the ultimate source of all
human DNA variations.