2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
c07.5
VLDLR (very low density lipoprotein receptor) is the first gene
implicated in cerebellar hypoplasia and quadrupedal locomotion
in humans
T. H. Ozcelik 1 , N. Akarsu 2 , E. Uz 1 , S. Caglayan 1 , S. Gulsuner 1 , O. E. Onat 1 , M.
Tan 3 , U. Tan 4 ;
1 Bilkent University, Ankara, Turkey, 2 Hacettepe University, Ankara, Turkey,
3 Baskent University, Ankara, Turkey, 4 Cukurova University, Adana, Turkey.
Quadrupedal gait in humans is a rare phenotype . We studied four
consanguineous families, reported as Unertan syndrome, all exhibiting
quadrupedal gait, dysarthric speech, mental retardation, and varying
degrees of cerebro-cerebellar hypoplasia . Homozygosity mapping
linked the locus for this unique autosomal-recessive trait to chromosome
9p24 in families A & D and 17p13 in family B . Family C excluded
linkage to both loci . These results suggest that hereditary disorders
associated with quadrupedal gait are genetically heterogenous . The
9p24 region includes the gene VLDLR, which is a component of the
reelin signaling pathway . Sequence analysis of VLDLR revealed two
distinct mutations, R257X in family A, and I780TfsX3 in family D . Both
of these mutations presumably truncate the protein, apparently leaving
behind a non-functional product . Unlike chromosome 9p24, the chromosome
17p interval is large and contains at least 157 genes . We
adopted a bioinformatics approach to screen the 17p interval for tri
nucleotide repeats GAA, CAG, CGG and CTG, and neuronal expression
. This analysis revealed several genes including lissencephaly-1
(LIS1, alternative symbol PAFAH1B1) . LIS1 interacts with VLDLR, and
heterozygous LIS1 mutations in humans cause lissencephaly I . Neither
LIS1 nor four additional genes (WDR81, RUTBC1, MNT, TRPV1)
showed an expansion of their repeat sequences . The search for the
chromosome 17p13 gene in Family B continues . Our data suggest
that mutations in VLDLR impair cerebro-cerebellar function and confer
a dramatic influence on gait in humans.
Supported by grants TUBITAK-SBAG 3334 and ICGEB-CRP/TUR04-
01 (to TO); Baskent University Research Fund KA 07/47 and TUBI-
TAK-SBAG-HD-230 (to MT) .
c07.6
The utilization of T3/T4 screening of males with MR of unknown
etiology to identify patients with Allan-Herndon-Dudley
syndrome
T. Wood 1 , D. Hobson 2 , B. Browning 1 , C. Rogers 1 , C. Skinner 1 , H. H. Ardinger 3 ,
F. Collins 4 , A. Aronsky 5 , M. J. Friez 1 , C. E. Schwartz 1 ;
1 Greenwood Genetic Center, Greenwood, SC, United States, 2 Wake Forest
University, Winston-Salem, NC, United States, 3 Children’s Mercy Hospitals and
Clinics, Kansas City, MO, United States, 4 Western Sydney Genetic Program,
Sydney, Australia, 5 Newark New Jersey, Newark, NJ, United States.
Allan-Herndon-Dudley syndrome (AHD; OMIM 309600) is an X-linked
recessive disorder presenting with hypotonia progressing to spasticity,
delay in developmental milestones, and severe mental retardation .
Mutations in the MCT8/SLC16A2 gene have shown to be causative in
clinically diagnosed AHD patients . MCT8 functions as a thyroid hormone
transporter with an essential function in the transport of triiodothyronine
(T3) into neurons . An imbalance of certain plasma thyroid
hormones has been identified in AHD patients. To investigate the
clinical utility of thyroid screening in patients with MR, we measured
free T3 and free T4 in a cohort of 137 males with MR of unknown
etiology. Twenty males were identified to have elevated T3 and molecular
analysis of MCT8 in these patients identified two (10%) with
pathogenic changes . One mutation was an insertion of 2 amino acids,
p .G41_S42 dup, in exon 1 . The 40 year old male had profound MR,
was ambulatory and non-verbal . He also had a seizure disorder and
a right spastic hemiparetic arm . The second mutation (p .G282C) was
in a 5 year old boy with truncal hypotonia and hypertonia of his extremities
with spasticity, dystonia and hyperreflexia - all consistent with
AHD . Additionally, 28 males enrolled in our XLMR study, with clinical or
biochemical evaluations suggestive of AHD, were analyzed for MCT8
mutations and seven (25%) had pathogenic changes . Based on our
results, testing the T3 level may serve as a general screen for the AHD
syndrome and should certainly be considered in males with significant
mental retardation and hypotonia .
c08.1
the role of the interferon regulatory factor 5 gene in
autoimmune diseases
G. Kristjansdottir 1 , S. Sigurdsson 1 , J. Sandling 1 , V. Dideberg 1,2 , H. Göring 3 , L.
Milani 1 , V. Bours 2 , F. Matesanz 4 , L. Rönnblom 5 , A. C. Syvänen 1 ;
1 Molecular medicine, Department of Medical Sciences, Uppsala University,
Uppsala, Sweden, 2 Department of Human Genetics, CHU de Liège, Liège,
Belgium, 3 Department of Genetics Southwest Foundation for Biomedical Research,
San Antonio, TX, United States, 4 Instituto de Parasitología y Biomedicina
López Neyra, Consejo Superior de Investigaciones Científicas, Granada,
Spain, 5 Section of Rheumatology, Department of Medical Sciences, Uppsala
University, Uppsala, Sweden.
IRF5 is a transcription factor involved both in the type I interferon and
toll-like receptor signalling pathways . We have found polymorphisms
in the IRF5 gene to be associated with several autoimmune diseases;
systemic lupus erythematosus 1 , rheumatoid arthritis 2 , multiple sclerosis
3 and inflammatory bowel disease 4 . By statistical methods two
variants in the IRF5 gene have been shown to be independently associated
to SLE . The variants are a CGGGG insertion-deletion (indel)
polymorphism located in the promoter region of the IRF5 gene and
a SNP rs10488631 located at the 3´end . The indel contains 3 or 4
repeats of the sequence CGGGG and the longer allele confers risk
to all of the autoimmune diseases tested . The risk allele contains an
additional binding site for the transcription factor SP1 . Using electrophoretic
mobility shift assays (EMSA) we observed allele-specific differences
in protein binding to the indel and by proximity ligation assay
(PLA) we demonstrated increased binding of the transcription factor
SP1 to the risk allele .
Our study adds to the evidence that there might be genes or pathways
that are common in multiple autoimmune diseases and that the type I
interferon system is likely to be involved in the development of these
diseases .
1) Sigurdsson S et al . Hum Mol Genet (2007) Dec 6
2) Sigurdsson S et al . Arthritis Rheum (2007) Jul;56(7):2202-10
4) Kristjansdottir G, Sandling J et al . J Med Genet accepted manuscript
3) Dideberg V et al . Hum Mol Genet (2007) Dec 15
c08.2
Elevated expression of serotonin receptor type 3 genes may
contribute to irritable bowel syndrome with diarrhea
J. Kapeller 1 , L. Houghton 2 , J. Walstab 3 , D. Möller 1 , H. Bönisch 3 , F. Autschbach 4 ,
N. Gassler 5 , C. Fischer 1 , P. Whorwell 2 , W. Atkinson 2 , C. Fell 2 , G. Rappold 1 , B.
Niesler 1 ;
1 Institute of Human Genetics, Heidelberg, Germany, 2 University of Manchester,
Manchester, United Kingdom, 3 Institute of Pharmacology and Toxicology, Bonn,
Germany, 4 Institute of Pathology, Heidelberg, Germany, 5 Institute of Pathology,
Aachen, Germany.
Serotonin type 3 (5-HT 3 ) receptor antagonists are beneficial in some
but not all patients with irritable bowel syndrome and diarrhea (IBS-D) .
As cis-regulatory variants can play a role in the etiology of complex
conditions by affecting efficiency of translation, we investigated the 5´
and 3´ untranslated region (UTR) of the 5-HT 3A and 5-HT 3E subunit
genes . Mutation analysis was carried out in 200 patients with irritable
bowel syndrome and 100 healthy controls . We found a HTR3A 5´UTR
variant and a novel HTR3E 3´UTR variant associated with the IBS-D
subtype. Functional studies showed that both variants lead to significant
upregulation of subunit expression . In HEK293 cells, the HTR3A
variant results in a higher density of 5-HT 3A receptors at the cell surface
compared to the wild-type control . The HTR3E variant affects a
microRNA binding site and leads to a higher luciferase reporter gene
expression . Both HTR3E and the miRNA co-localize in enterocytes
of the mucosal cell layer of the gut epithelium as shown by in situ
hybridization . We suggest that the increased expression of 5-HT 3A and
5-HT 3E subunits might result in a change in 5-HT 3 receptor composition
and/or density of 5-HT 3 receptors in the epithelial cell layer of the mucosa
and neurons of the enteric and central nervous system and could
therefore contribute to the pathophysiology of IBS-D .