2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association 0
in the protomutation ranges, 51-60, 61-70 and 71-80 repeats, respectively.
For the transmitting females, full mutations were only seen in the
71-80 repeat range, and in 5/6 (83%) offspring.
In conclusion, paternal repeat length instability occurs frequently and
mainly between 51-80 repeats, while maternal repeat length instability
occurs infrequently and only above 70 repeats. This observation has
implications for genetic counseling.
P16.54
Unusual splice site mutation involved in a fatal form of tK2
associated mitochondrial DNA depletion myopathy
W. M. Schmidt 1 , M. Steiner 1 , D. Jovanovic 1 , B. Dellinger 1 , K. Moser-Thier 1 , R.
Wegscheider 1 , M. Freilinger 2 , R. Seidl 2 , E. Hauser 3 , R. E. Bittner 1 ;
1 Neuromuscular Research Department, Center of Anatomy & Cell Biology,
Medical University of Vienna, Vienna, Austria, 2 Department of Pediatrics, Medical
University of Vienna, Vienna, Austria, 3 Landesklinikum Thermenregion
Mödling, Austria.
Mutations in the TK2 gene are associated with the autosomal recessive
mtDNA depletion myopathy. Here, we describe two dizygotic twins
who developed progressive, severe muscle hypotonia by age of 10
months. Both had elevated serum CK (>1000 U/L) and MRI disclosed
marked cortical atrophy. Muscle biopsy revealed red-ragged fibres,
multiple sarcoplasmic vacuoles, and numerous cytochrome-c-oxidase
negative fibres. Activities of respiratory chain enzymes were massively
reduced. After detection of pronounced mtDNA copy number reduction
in muscle, we sequenced TK2.
We found compound heterozygosity for two mutations in both siblings:
c.542C>T (p.A181V) and c.665-7A>G (IVS7). The mother was
heterozygous for c.542C>T, and the father carried the heterozygous
c.665-7A>G mutation. Whereas pathogenicity of c.542C>T had been
previously established, the second mutation has not been reported so
far. Several in silico predictions for this mutation, which affects position
-7 of the IVS7 acceptor splice site, failed to suggest any detrimental
effect on splicing. To investigate the potential pathogenicity
of this intronic base substitution, RNA isolated from peripheral blood
was subjected to RT-PCR analysis, revealing that the mutation creates
an aberrant acceptor splice site leading to inclusion of extra nucleotides
(r.664_665insCCTCAG). This aberrant splicing pattern ultimately
causes the predictable intolerable insertion of two additional amino
acids [p.(221_222insAlaSer)] into a highly conserved motif within the
deoxyribonucleoside kinase domain.
Our work not only extends the TK2 mutational spectrum, it also highlights
the importance of experimental analysis of intronic mutations
detected during routine DNA diagnostics procedures, because algorithms
to predict a splicing defect were uninformative in our case.
P17. Genetic analysis, linkage ans association
P17.01
common variants near MC R are associated with general and
visceral adiposity in European- and African-American Youth
G. Liu 1 , H. Zhu 2 , V. Lagou 1 , B. Gutin 2 , F. A. Treiber 2 , Y. Dong 2 , H. Snieder 1,2 ;
1 University Medical Center Groningen, University of Groningen, Groningen, The
Netherlands, 2 Georgia Prevention Institute, Department of Pediatrics, Medical
College of Georgia, Augusta, GA, United States.
Objectives: Rare functional mutations of melanocortin 4 receptor
(MC4R) are the leading cause of monogenic severe childhood-onset
obesity. Recent genome-wide association studies (GWAS) found common
variants near MC4R associated with obesity and insulin resistance
(IR). This study aimed to assess the influence of the identified
single nucleotide polymorphisms (SNPs) rs17782313 and rs17700633
on general and visceral adiposity, and on IR in European-American
(EA) and African-American (AA) youth.
Methods: In 1902 youth (48.9% European-American, 45.4% male, mean
age 16.2 years), we examined the associations of the rs17782313 and
rs17700633 with anthropometry, percent body fat (%BF) and visceral
adipose tissue (VAT). Interactions of the SNPs with ethnicity or gender
were investigated and haplotype analyses conducted.
Results: Significant associations were found between rs17782313 and
body mass index (BMI) (P=0.004), weight (P=0.002), waist circumference
(P=0.004), and sum of skinfolds (P=0.032), explaining between
0.30% and 1.0% of variance. Rs17700633 was significantly associated
with %BF (P=0.018) and VAT (P=0.006), explaining 0.57% and 1.67%
of the variance, respectively. No significant interactions of the variants
with ethnicity or gender were found for any of the obesity-related
phenotypes. Compared to the most common haplotype, the haplotype
with both minor alleles showed higher weight (P=0.002), BMI (P=0.02),
%BF (P=0.004) and VAT (P=0.02). No significant effects were found
on indices of IR after adjustment for BMI.
Conclusions: The relatively large effect of these common variants near
MC4R with general and visceral adiposity in childhood could prove
helpful in elucidating the molecular mechanisms underlying the development
of obesity in early life.
P17.02
the frequencies of polymorphic alleles +49A/G CTLA , -1858c/t
PTPN and -23HphiA/t INS genes in Belarusian population and
diabetic patients.
E. Aksyonova1 , T. Pokladok1 , D. Boiko1 , L. Viasova2 , A. Solntsava2 , N. Danilenko1
;
1 2 Institute of Genetics and Cytology, Minsk, Belarus, Belarusian State Medical
University, Minsk, Belarus.
Various genes were proved to control predisposition to autoimmune
diabetes (T1D). Our aim was to study the genotype frequencies of
+49A/G CTLA4; 1858C/T PTPN22 and -23HphIA/T INS and their combinations
in healthy Belarusians and diabetic patients. 474 native Belarusians
from 6 ethnogeographic regions; 20 patients with comorbidity
of autoimmune thyroid disease (AITD) and type 1 diabetes, as well
as 23 type 1 diabetic patients were genotyped. The risk genotype GG-
TT-AA (CTLA4-PTPN22-INS respectively) was revealed in 6 individuals
(1,27 %) of ethnic population. 14 individuals (2,95 %) possessed
protective homozygous genotype (AA-CC-TT) and 35 individuals (7,4
%) were heterozygotes at all loci. The comparative study of CTLA4-
PTPN22 genotype frequencies was conducted in 741 individuals from
6 ethnogeographic regions. The most common genotype GA-CC
(heterozygous of +49A/G CTLA4 locus and homozygous of 1858C/
T PTPN22 locus) was revealed in 33,9 % of population studied. The
protective genotype (AA-CC) was detected in 22,5 % of investigated
Belarusians. The risk genotype (GG-TT) frequency was low - 0,9%. In
diabetic subjects the risk genotype GG-TT-AA (CTLA4-PTPN22-INS
respectively) was revealed in 1 case (2,3%). The GA-CT-AA genotype
frequency was significantly (P