2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
Tandem Repeat markers (STR) and KRT86 gene was sequenced for
the identification of the disease causing mutation. In the results of this,
autosomal dominant mutation (E402K) in exon 7 of KRT86 gene was
identified as a cause of Moniltherix in the large family from Turkey.
P05.214
PEX7 gene mutation in infant with Rhizomelic chondrodysplasia
Punctata type 1
M. G. Ogur1 , C. Has2 , A. Yıldıran1 , P. Baysal1 , H. R. Waterham2 ;
1 2 Ondokuz Mayis University Medical Faculty, Samsun, Turkey, Academic Medical
Center, University of Amsterdam, Amsterdam, Netherlands.
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive
peroxisomal disorder. Clinically patients present dwarfism due to
symmetrical shortening of proximal long bones, ataracts, periarticular
calcifications, multiple joint contractures, and psychomotor retardation.
So far three subgroups have been defined due to different genes involved
. The most common of these is RCDP Type 1 which is caused
by mutations in PEX7 gene .
Here we report a 4 year 6/12 month-old male infant diagnosed as RCDP
due to distinct clinical manifestations: short stature, rhizomelic shortening
of proximal long bones, multiple joint contractures, and psycomotor
retardation. There was notable frontal bossing, depressed profile,
a flat nasal bridge, dysplastic external ears, and small nares. Roentgenological
studies included abnormalities such as severe shortening
of the femur and humerus, irregular and broad metaphyses, calcific
stippling of the epiphyses (humerus) . Bilateral cataract was diagnosed
later . Plasma phytanic acid levels were elevated . Mutation analysis for
PEX7 gene revealed a homozygous mutation for 370_396del127bp
(del G124_S132) .
The parents were consanguineous and the family history yielded
another similarly affected and deceased female child . After mutation
analysis family was informed and data given for possibilities of a prenatal
diagnosis in any subsequent pregnancy .
P05.215
Identification of a novel mutation in DKC1 in Russian family with
Dyskeratosis congenita
M. Kurnikova 1 , I. Shagina 1 , M. Maschan 2 , A. Maschan 2 , L. Khachatryan 2 , D.
Shagin 1,3 ;
1 Evrogen Joint Stock Company, Moscow, Russian Federation, 2 Federal Research
Clinical Center for pediatric hematology, oncology and immunology,
Moscow, Russian Federation, 3 Shemyakin and Ovchinnikov Institute of Bioorganic
Chemistry, Moscow, Russian Federation.
Dyskeratosis congenita (DC) is a rare congenital syndrome characterized
by the triad of reticular skin pigmentation, nail dystrophy and
mucosal leukoplakia, and the predisposition to bone marrow failure
and malignancies . Mutations in DKC1 gene encoding dyskerin are responsible
for the X-linked DC . We found novel mutation in DKC1 in
Russian family with X-linked DC . The proband was a 10-y-old boy with
skin lesions, nail dystrophy, oral mucosa erosions, epiphora and blood
marrow failure, and his 8-y-old brother had identical signs of ectodermal
dysplasia without bone marrow failure . Their 2-y-old sister had no
clinical signs of DC . Each of the 15 coding exons of the DKC1 gene
and their flanking regions were amplified from genomic DNA by PCR
and screened for mutations by SSCP analysis, and the shift detected
on the SSCP gel was re-amplified, cloned and sequenced. The novel
mutation is a 2-bp inversion in exon 3: NM_001363:c .166_167invCT
(L55S) . It was found in the proband and his brother; their mother was a
carrier and the sister was not. This is the first report of DKC1 mutation
analysis in Russian patients .
P05.216
Human developmental biology resource
D. Gerrelli1 , S. Lisgo2 , A. J. Copp1 , S. Lindsay2 ;
1 2 Institute of Child Health, London, United Kingdom, Institute of Human Genetics,
Newcastle, United Kingdom.
The Human Developmental Biology Resource (HDBR) is a unique
resource, funded by the Wellcome Trust and UK-MRC to provide human
embryonic and fetal tissue to the research community for gene
expression studies . The HDBR is based at the Institute of Child Health,
University College London and the Institute of Human Genetics, Newcastle
University . The HDBR collects material from terminations of
pregnancy . This valuable material is used primarily to study the ex-
pression of developmentally significant genes including genes implicated
in birth defects and inherited metabolic disorders .
The HDBR has ethical approval for the collection, storage and distribution
of material between 4 and 12 weeks of development . Ethics
Committee approval and a laboratory Risk Assessment is required before
material can be supplied . The HDBR can provide fresh, frozen or
sectioned material . In addition the HDBR administers the Fetal Tissue
Bank (FTB) collection, previously at the Hammersmith Hospital . The
FTB collection is composed of material between 8 and 19 weeks of
gestation and is either frozen or cryopreserved for the generation of
cell lines. A significant proportion of the HDBR material is karyotyped
and normal karyotyped material is provided for research but karyotypically
abnormal material can be provided on request .
In addition the HDBR offers an in-house gene expression service for
the analysis of RNA or protein using in situ hybridisation or immunohistochemistry
respectively . The HDBR provides electronic images for
publication and advice on interpretation of results . Data is deposited,
in a public database .
Data from recent HDBR studies will be presented .
P05.217
Renal damage triggers cyst formation in an inducible Pkd -
deletion model
H. Happé1 , A.M. van der Wal 2 , I.S. Lantinga-van-Leeuwen1 , W.N. Leonhard1 ,
M.H. Breuning1 , E. de Heer2 and D.J.M. Peters1 ;
1 2 Human Genetics, Leiden University Medical Center, Pathology, Leiden University
Medical Center
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused
by a mutation in the PKD1 or PKD2 gene . This disease is characterized
by large fluid-filled kidney cysts and a progressive deterioration of
renal function eventually leading to renal replacement therapy .
We generated a tamoxifen-inducible, kidney epithelium-specific Pkd1deletion
mouse model . Deletion of the Pkd1 gene in adult mice resulted
in a mild cystic phenotype . However, in newborn mice, this results
in massive cyst formation . In young mice, tubular cell proliferation still
takes place to elongate the nephron, in contrast to the adult kidney .
Therefore, we hypothesized that renal injury followed by a tissue repair
response, including epithelial cell proliferation, accelerates cyst formation
in adult Pkd1-deletion mice .
Inducible Pkd1-deletion mice were treated with the nephrotoxicant
DCVC upon Pkd1-gene inactivation . 10-14 weeks after DCVC treatment,
renal function rapidly declined in DCVC treated Pkd1-deletion
mice, as determined by blood urea concentration . Kidney-to-body
weight ratios were increased in DCVC treated animals compared to
controls . Histopathological analysis revealed numerous cysts mainly
of proximal tubular origin . Cyst formation was absent in DCVC treated
Pkd1 +/- mice while non-treated Pkd1-deletion mice only showed few focal
cysts . Renal proliferation indexes were determined by Ki-67 staining
at 1 wk after injury and were increased in Pkd1-deletion animals
compared to DCVC treated Pkd1 +/- mice .
In conclusion, these data provide evidence that injury-induced enhanced
proliferation of renal epithelium in the absence of wild type
polycystin-1 is a trigger for cyst formation . Since polycystin-1 localizes
in the basal-body/centrosome, we hypothesize that aberrant planar
cell polarity of the newly formed cells plays a role in ADPKD .