2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
ings strongly suggest that PQBP1 plays a hitherto unknown role in
post-transcriptional RNA regulation and metabolism. Disturbance of
one or several of these processes may contribute to the clinical phenotype
in patients with a PQBP1 mutation.
P02.200
A recurrent copy number gain at Xq28 in four families with
mental retardation reveals a dosage-dependent severity of the
phenotype and suggests a novel recombination mechanism
H. Van Esch 1 , J. Vandewalle 2 , K. Govaerts 2 , C. Zweier 3 , I. Madrigal 4 , M. Mila 4 ,
I. Fernandez 5 , D. Böhm 6 , C. Spaich 7 , J. Kohlhase 6 , A. Rauch 3 , P. Marynen 2 , J.
Fryns 1 , G. Froyen 2 ;
1 Center for Human Genetics, Leuven, Belgium, 2 Center for Human Genetics,
Human Genome Laboratory, Leuven, Belgium, 3 Institute of Human Genetics,
University Hospital Erlangen, Erlangen, Germany, 4 Biochemistry and Molecular
Genetics Department Hospital Clínic, Institut d’Investigacions Biomèdiques
August Pi i Sunyer and CIBERER, Barcelona, Spain, 5 Instituto de Biología y
Genética Molecular, Universidad de Valladolid, Valladolid, Spain, 6 Center for
Human Genetics Freiburg, Freiburg, Germany, 7 Institute for Clinical Genetics,
Olgahospital, Stuttgart, Germany.
In a study to elucidate the genetic defects in patients with X-linked
mental retardation (XLMR) we performed X chromosome-specific
BAC-array-CGH and identified a 0.3 Mb inherited apparent recurrent
copy number gain at Xq28 in affected males of four unrelated XLMR
families. All aberrations segregate with the disease and the carrier
mothers show nonrandom X-inactivation. Interestingly, this region was
duplicated in two families with nonsyndromic mild to moderate MR,
triplicated in a third family with more severe characteristics, while in a
fourth family with severe syndromic MR, this region was present in four
copies. The aberrant region is located at 153.21 Mb to 153.53 Mb and
harbors 18 genes of which three are highly expressed in brain (RPL10,
ATP6AP1, GDI1). Expression analysis revealed copy number-dependent
increased mRNA levels in affected patients compared to controls,
which correlates with the severity of clinical features. Our data strongly
suggest that an increased expression of genes within this region results
in impaired cognition in a dosage-dependent manner. Breakpoint
analysis revealed recombination sites within two adjacent sets of low
copy repeats which implies a yet unknown recombination mechanism.
Finally, in patients with MECP2 duplication the region described in this
study is often completely or partially involved, but the contribution of
their increased mRNA expression to the severe phenotype is probably
masked by the strong effect of increased MeCP2 levels. Our data thus
demonstrate that a copy number gain of individual genes present in a
contiguous genomic aberration can on itself result in a clinical phenotype
too.
P02.201
transcriptional behaviour of SLC A gene mutant alleles in
creatine transport deficient patients
P. Alcaide 1 , B. Merinero 1 , A. Ribes 2 , R. Artuch 3 , J. Campistol 3 , M. Ugarte 1 , P.
Rodriguez-Pombo 1 ;
1 Centro Biologia Molecular SO (CSIC-UAM) CIBERER, Madrid, Spain, 2 Instituto
de Bioquímica Clínica.CIBERER, Barcelona, Spain, 3 Hospital San Joan de
Deu.CIBERER, Barcelona, Spain.
In mammals, creatine (Cr) is taken from diet or can be synthesized
endogenously. Creatine uptake by cells with high energy demands
depends on a specific creatine transporter, CT1 encoded by SLC6A8
gene. Although there are about 20 pathogenic variations described
for the SLC6A8 gene, their transcriptional profile has been poorly
studied. Here, we focus our interest in characterizing at mRNA level
three in-frame mutations p.Ala404Pro, p.Phe360del and p.Phe480del,
identified in three Spanish CT1 patients with a clinical presentation
of the disease ranging from less to more severe. We performed both
RT-PCR analysis to characterize possible exon skipping events and
quantification of SLC6A8 mRNA levels using qRT-PCR. The cDNA behaviour
did not show any aberrant splicing, failing to explain their different
clinical phenotype. However, a different expression profile of the
SLC6A8 gene in the three CT1 patient’s fibroblasts was observed. So,
alleles causing a phenylalanine deletion showed a significative reduction
in the SLC6A8 mRNA levels, when compared to that measured
for p.A404P allele or controls. To analyse if these changes could trigger
mRNA degradation, patient’s fibroblast were treated with different
inhibitors of both protein synthesis and non mediated decay process
00
(NMD) such as emetine and puromicine. An 8 and 2 fold recoveries
of SLC6A8 levels were obtained for p.Phe480del and p.Phe360del
respectively, when compares to corresponding controls. We hypothesised,
that a reduced expression of SLC6A8 gene, probably related
to mRNA instability, could be relevant to explain the more severe presentation
of the disease in these two patients.
P02.202
Autosomal dominant hereditary spastic paraplegia with dystonia
in two Russian families
G. E. Rudenskaya 1 , E. L. Dadaly 1 , V. Strelnikov 2,3 ;
1 Medical Genetics Research Center, Moscow, Russian Federation, 2 Research
Centre for Medical Genetics, Moscow, Russian Federation, 3 Institute for Molecular
Medicine, Moscow Medical Academy, Moscow, Russian Federation.
Dystonia (DYS) is a very rare feature in ‘complicated’ hereditary spastic
paraplegias (HSP+). In 2008, Gilbert et al described a large family
with autosomal dominant (AD) HSP+DYS and mapped the locus
in 2q24-q31. We diagnosed AD HSP+DYS in two families. Family 1
numbered 4 patients, a 31-year-old proband, her 40-year-old brother,
their father, and her 2.5 year-old son. In the proband, severe spastic
paraplegia (SP) started in childhood; DYS presented in 11 yrs as
writer’s cramp and then as torticollis, in 27 yrs DYS in hands started;
yet, SP prevailed. Her son had severe SP since infancy looking like
spastic cerebral palsy; followed up to 8 yrs he was non-ambulatory,
with normal mental development and no DYS. In the not-examined
brother, SP presented since youth as ‘shuffling’ gait; DYS started at 28
yrs as torticollis and progressed to a severe generalized form resistant
to treatment and prevailing over SP. The father had ‘shuffling’ gait till
50 yrs when the gait deteriorated rapidly; dementia and psychosis also
developed; he died in 54 yrs non-ambulatory and mentally disabled.
In Family 2, 24-year-old male proband was examined. SP and DYS
started in 7_8 yrs and progressed with generalized DOPA-resistant
DYS prevailing over SP. Proband’s father died in 58 yrs with no evident
symptoms; deceased paternal grandmother and her sister were said to
have adult-onset generalized hyperkinesia. Intrafamilial variability and
anticipiation are seen in both families. Family 2 suggests incomplete
penetrance. Origin of dementia in the father in Family 1 is questionable.
P02.203
Atypical clinical presentation of leukoencephalopathy with brain
stem and spinal cord involvement and lactate elevation (LBsL)
S. V. Mikhailova 1 , G. E. Rudenskaya 2 , E. Y. Volkova 1 , E. Y. Zakharova 2 , V.
Strelnikov 3,4 ;
1 Russian State Pediatrics Hospital, Moscow, Russian Federation, 2 Medical
Genetics Research Center, Moscow, Russian Federation, 3 Research Centre for
Medical Genetics, Moscow, Russian Federation, 4 Institute for Molecular Medicine,
Moscow Medical Academy, Moscow, Russian Federation.
LBSL, MIM 611105, is a “new” autosomal recessive disease with distinctive
MRI and spectroscopy features. The causative gene DARS2
codes mitochondrial aspartyl-tRNA synthetase. Along with some other
recently described leukoencephalopathies, LBSL proved to be a not infrequent
disorder. In the Department of metabolic disorders of Medical
Genetics Research Center, 35 unrelated LBSL cases were verified by
DNA analysis since 2007. Typical features are childhood onset, slowly
progressive cerebellar ataxia, spasticity, and dorsal column dysfunction.
We present a 12-year-old female patient with atypical feature
of paroxysmal dyskinesias. They started in 1.5 yrs during a common
febrile infection and reappeared, produced by motion, as involuntary
body turn to the right with putting right leg aside and crying. Later on,
paroxysms became persistent and of different appearance. By now,
they occur many times a day, mostly in the beginning of motion after
rest, and look like abrupt quick legs flexion with sitting on the ground
for few instants, or just like legs flexion if the girl is in a sitting position.
Other signs are moderate spasticity and ataxia; mental development
is normal. Epilepsy, electrolyte disbalance, myotonia, and psychogenic
disorder were excluded. LBSL was diagnosed in 12 yrs when MRI was
recognized as characteristic for the disease. Compound heterozygosity
for common DARS2 mutations, c.228-20_21delTTinsC and c.455G-
T, was found. To our knowledge, paroxysmal dyskinesias in LBSL were
not described previously; their persistence through many years is also
remarkable. The dyskinesias may be of brain stem origin, like those in
multiple sclerosis or brain stem stroke.