2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
those evidences, we established hat other IP-associated NEMO mutations,
such as E57K and DeltaK90 showed a defective interaction with
TRAF6. The sum of this observation supports the view that multiple
signal modifications, mainly polyubiquitination, that converge at NEMO
are necessary events in IKK activation whose perturbation may cause
human pathophysiology.
P12.116
conventional mutations are associated with a different
phenotype than polyglutamine expansions in spinocerebellar
ataxias
A. Durr1,2 , G. stevanin1,2 , S. Forlani1 , C. Cazeneuve2 , C. Cagnoli3 , K. P.
Figueroa4 , D. Lorenzo5 , J. Johnson6 , J. van de Leemput6 , M. Viemont2 , A.
Camuzat1 , A. Singleton6 , L. Ranum5 , S. Pulst4 , A. Brusco3 , E. Le Guern2 , A.
Brice1,2 ;
1 2 CRicm UMRS975/NEB, Paris, France, Département de Génétique et Cytogénétique,
Paris, France, 3Department of Genetics, Biology and Biochemistry,
Torino, Italy, 4Cedars-Sinai Medical Center, Los Angeles, CA, United States,
5 6 University of Minnesota, Minneapolis, MN, United States, National Institute on
Aging, NIH, Bethesda, MD, United States.
Autosomal dominant cerebellar ataxias comprise a wide spectrum of
diseases with different clinical/neuropathological profiles. At least 30
responsible loci (SCA) have been mapped. Nucleotide repeat expansions
have been identified as responsible for the disease in 9 genes
including those caused by polyglutamine-coding (CAG)n repeat expansions
in the SCA1-3,6,7 and 17 genes and rare forms caused by
non-coding repeats in the SCA8,10 and 12 genes. More recently, conventional
mutations were reported in SPTBN2/SCA5, TTBK2/SCA11,
KCNC3/SCA13, PRKCG/SCA14, ITPR1/SCA15/16, FGF14/SCA27,
AFG3L2/SCA28 as well as in the puratrophin gene.
The relative prevalence of the SCA genes and their associated phenotype
was investigated in 826 index patients from families with a dominant
transmission of the disease collected from 1990 to 2008 in the
Pitié-Salpêtrière university-hospital in Paris or through clinical national
networks using standardized clinical charts.
The most frequently mutated genes were SCA3 (20.4%), SCA2 (9.7%),
SCA1 (7.7%), SCA7 (5.7%) and SCA6 (1.8%). Missense mutations in
SCA14 (1.8%), SCA28 (1.6%), SCA13 (1.2%) and SCA5 (0.8%) were
less frequent. We found SCA17 (0.2%) and SCA12 (0.2%) to be very
rare, while no cases of SCA10, 27 or puratrophin were identified. In
subclinical selections, heterozygous deletions in SCA15/16 (4/76) and
a non-sense mutation in SCA11 (1/77) were also detected.
Genotype-phenotype correlations showed that CAG repeat expansion
diseases shared a rapidly progressive and severe disease course with
onset in the thirties. On the contrary, the clinical picture associated
with conventional mutations in the recently identified genes was milder
despite the frequent presence of marked cerebellar atrophy on MRI.
P12.117
Nance-Horan syndrome and X-linked cataract are allelic
disorders
M. Coccia 1 , S. P. Brooks 1 , T. R. Webb 1 , K. Christodoulou 1 , V. Murday 2 , M.
Balicki 3 , T. Wangensteen 4 , S. Park 5 , E. R. Maher 6 , A. A. Moore 7 , I. M. Russell-
Eggitt 8 ;
1 UCL Institute of Ophthalmology, London, United Kingdom, 2 Yorkhill Hospital,
Glasgow, United Kingdom, 3 The hospital for sick children, Toronto, ON, Canada,
4 Ulleval University Hospital, Oslo, Norway, 5 Addenbrooke’s Hospital, Cambridge,
United Kingdom, 6 Birmingham Women’s Hospital, Birmingham, United
Kingdom, 7 Moorfields Eye Hospital, London, United Kingdom, 8 Great Ormond
Street Hospital for Children, London, United Kingdom.
Nance-Horan syndrome (NHS) is an X-linked developmental disorder
characterised by congenital cataract, dental anomalies, facial dysmorphism,
and in some cases, mental retardation. Protein truncation
mutations in a novel gene (NHS) have been identified in patients with
this syndrome. Isolated X-linked congenital cataract (CXN) has been
mapped to chromosome Xp22.13, which encompasses the NHS locus,
however, no mutations were identified in the NHS gene. In this study
we describe a clinical and molecular analysis of 7 NHS and 2 CXN
families. We have identified five new protein truncation mutations and
a large deletion encompassing the majority of the NHS gene in NHS
families. Two CXN families, who were negative for mutations in the
NHS gene, were further analysed using array comparative genomic
hybridisation (CGH). We show, for the first time, that these diseases
are indeed allelic. Interestingly, all mutations in the NHS gene causing
Nance-Horan Syndrome are protein truncating mutations. In contrast,
two X-linked cataract families have different copy number variations
of the NHS gene; an intragenic deletion and a complex duplicationtriplication
rearrangement. We suggest that both of these mutational
events lead to altered transcriptional regulation of the NHS gene leading
to a milder phenotype than Nance-Horan syndrome. Analysis of
the position and sequences of the breakpoints pinpoints regulatory
sequences for NHS gene expression, and also potential molecular
mechanisms for non-recurrent non-homologous recombination. Our
data show the importance of different mutational mechanisms leading
to different severities of disease.
P12.118
Possible involvement of N-acetyltransferase 2 in development of
endometriosis
E. Kamenec 1 , L. F. Kurilo 1 , A. V. Polyakov 1 , L. M. Michaleva 2 , A. A. Solomatina
3 , N. V. Sikorskaya 4 ;
1 Reseach Centre for Medical Genetics, Moscow, Russian Federation, 2 Institute
of Human Morphology RAMS, Moscow, Russian Federation, 3 Russian State
Medical University, Moscow, Russian Federation, 4 Municipal Clinical Hospital #
31, Moscow, Russian Federation.
Endometriosis is a common disease defined as a growth of endometrial
tissue outside the uterine cavity that often results a vast array of gynaecological
problems including dysmenorrhoea, pelvic pain, infertility.
Basic aetiology and pathogenesis of this condition isn’t clearly enough.
Endometriosis is regarded as one of the multifactorial diseases caused
by an interaction between the environment and multiple genes.
N-acetyltransferase 2 is the enzyme realized N-acetylation and biotransformation
of xenobiotics. NAT2 slow genotypes affect detoxification
function and might increase the risk of the disorder. The present
study was carried out to investigate if polymorphisms of NAT2 are useful
markers for predicting endometriosis susceptibility.
DNA was extracted from blood of 86 patients with reliable diagnosis
of endometriosis and 53 healthy women (control group). NAT2 gene
polymorphism was detected in five polymorphic sites: c.341T>C,
c.481C>T, c.590G>A, c.803A>G, c.857G>A. PCR-PFLP analysis
was applied to detect the missense substitution in nt position 590 and
MLPA for others. The relative frequencies of the polymorphisms between
both groups were compared.
The proportions of individuals homozygous for c.341C, c.590A, and
c.803G were 18.6 and 11.3%, 7.0 and 5.6%, 19.8 and 9.4% in the
endometriosis and control groups accordingly (P > 0.05). There were
no individuals homozygous for c.857A in both groups. The proportion
of c.481T homozygous individuals was 30.2% in patients and 7.5%
in controls that corresponded to significantly difference between two
groups (P = 0.001). These results show the significant impact of NAT2
gene polymorphism in position 481 in development of endometriosis.
P12.119
NPHS and WT gene mutations in Greek children with steroid
resistant nephrotic syndrome (sRNs)
E. Fylaktou 1 , S. Megremis 1 , A. G. Mitsioni 1 , A. Mitsioni 2 , C. J. Stefanidis 2 , S.
Kitsiou-Tzeli 1 , E. Georgaki 3 , E. Kanavakis 1 , J. Traeger-Synodinos 1 ;
1 Medical Genetics, Athens University, Athens, Greece, 2 Dept Pediatric Nephrology,
“P. A. Kyriakou” Children’s Hospital, Athens, Greece, 3 Dept Pediatric Nephrology,
“Aghia Sophia” Children’s Hospital, Athens, Greece.
Several genes are implicated in the pathogenesis of autosomal recessive
SRNS, including NPHS2 (encoding podocin) and WT1(transcription
factor Wilm´s tumor-1). The presence of mutations in the 8 exons of
the NPHS2 gene, along with “hot-spot” exons 8 and 9 of the WT1
gene, were investigated (direct sequencing) in 27 SRNS patients (2-18
years), including 8 familial (3 families) and 19 sporadic cases.
NPHS2 analysis revealed pathogenic genotypes in 3/19 sporadic patients:
homozygosity for R138Q (c.413G>A), homozygosity for R168H
(c.503G>A) and compound heterozygosity for R229Q (c.686G>A) in
trans to A295T (c.883G>A). The novel A295T (exon 8) is predicted
to be pathogenic by in silico assessment. Amongst familial cases, 3
patients were heterozygous for R229Q without a second NPHS2 mutation.
Additionally, several known polymorphisms (IVS3-46C>T, IVS3-
21C>T, IVS7+7A>G, S96S, A318A, and L346L) were found in both
patients and 100 unaffected controls with equal allele frequencies. A
novel intronic NPHS2 variant (IVS3-17C>T), was found in 2 related