More ESHG 2008 abstracts

Study of mtDNA polymorphism in type 2 diabetes patients
S. V. Buikin1, M. V. Golubenko1, K. V. Puzyrev2, O. A. Makeeva1, I. V. Tsimbaluk3, O. A. Koshelskaja2, V. P. Puzyrev1;
1Research Institute of Medical Genetics, Tomsk, Russian Federation, 2Research Institute of Cardiology, Tomsk, Russian Federation, 3Siberian State Medical University, Tomsk, Russian Federation.
Presentation Number: P06.298
Diabetes is among frequent endocrine diseases. Endocrine system is one of energy-dependent systems in human organism. Phylogenetic mtDNA haplogroups possess different common polymorphisms and can mark effects of these variants on predisposition to common diseases. Samples of 119 type 2 diabetes patients (78 women, 41 men) and 134 healthy people were studied (all living in Tomsk region). Mean age in the groups was 52+5.5 and 47.6+10.2 years, respectively. Ultrasound examination, 24-hours monitoring of blood pressure and fasting glucose measure were performed. Comparison of frequencies of some of Europeans haplogroups (H, U, T, J) has uncovered lower frequency of haplogroup T in type 2 diabetes patients as compared to control group (OR=0.14; 0.02OR0.66; p=0.007). In the group of type 2 diabetes patients this haplogroup was detected only in two cases, whereas in control it corresponds to known frequencies for European population (11.6%). Our previous study which was conducted on patients with arterial hypertension has shown higher prevalence of haplogroup T in group of patients with left ventricular hypertrophy against patients without this complication. These alternative effects of mitochondrial haplogroup T may reflect different adaptive advantages for an individual carrying the haplogroup, in respect to different conditions. The findings suggest that particular mtDNA haplogroup (i.e. set of haplogroup-specific polymorphisms in mtDNA) may have some impact on energy metabolism and may be predisposing or protective factor for some diseases and their complications. The work was supported by Russian Foundation for Basic research (RFBR) grants 07-04-01526, 06-04-08326.


Hierarchical analysis of 28 Y-chromosome SNP’s in the population of the Republic of Macedonia
P. Noveski, S. Trivodalieva, G. D. Efremov, D. Plaseska-Karanfilska;
Macedonian Academy of Sciences and Arts, Research Centre for Genetic Engineering and Biotechnology, Skopje, Macedonia, The Former Yugoslav Republic of.
Presentation Number: P05.211
Analysis of Y-chromosome haplogroups, defined by single nucleotide polymorphisms (SNP’s), has become a standard approach for studying the origin of human populations and measuring the variability among them. Furthermore, Y-SNP’s represent a new forensic tool, because their population specificity may allow to determine the origin of any male sample of interest for forensic purposes. The aim of this study was to develop a strategy for rapid, simple and inexpensive Y-chromosome SNP’s typing in the population of R. Macedonia. We have studied a total of 343 DNA male samples; 211 Macedonians, 111 Albanians and 21 of other ethnic origin (Roma, Serbs and Turks). Methodology included multiplex PCR and single nucleotide extension reaction by SNaPshot multiplex kit. The set of 28 markers has been grouped in 5 multiplexes in order to determine the most frequent haplogroups using only 1 or 2 multiplexes. Twenty different Y haplogroups were determined among 343 male DNA samples. The finding that five haplogroups (E3b1, I1b1, J2b1a, R1a and R1b) comprise more than 70% of the Y chromosomes is consistent with the typical European Y chromosome gene pool. The distribution of the Y-haplogroups differs between Macedonians and Albanians. The most common Y haplogroup among Macedonians is I1b1 (27.5%), followed by three haplogroups present with similar frequencies E3b1 (15.6%), R1a (14.2%) and R1b (11.4%). Among Albanians the most frequent Y haplogroup is E3b1 (28.8%), followed by R1b (18.0%), J2b1a (13.5%) and R1a (12.6%).


The genetic causes of sex differences in neurodevelopmental disorders
E. Stergiakouli, H. Williams, K. Langley, A. Thapar, M. J. Owen;
Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
Presentation Number: P06.006
ADHD and schizophrenia are heritable, neurodevelopmental disorders that are more prevalent in males. Both disorders also show sex differences in age of onset and severity. The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. Animal models have associated the Y chromosome with aggression and decreased levels of serotonin and dopamine in the brain. However, due to difficulties arising from the lack of recombination and widely accepted nomenclature, the Y chromosome has been largely excluded from genetic and genomic studies of neuropsychiatric disorders. . In order to overcome this lack of knowledge we chose to study the Y chromosome in a sample of 210 cases with ADHD, 310 cases with schizophrenia and 700 U.K. controls. In total, 40 Y chromosome markers were selected to represent the main Y chromosome haplogroups that are present in the U.K. according to data from the Y chromosome Consortium data and personal communication with Y chromosome researchers. Statistical analysis of Y chromosome haplogroup analysis revealed no significantly increased representation of any haplogroup in cases with ADHD or schizophrenia compared to controls. However, this is one of the few studies to have genotyped Y chromosome markers in such a large number of U.K. individuals and therefore our results provide an insight into the population structure of U.K. Y chromosome haplogroups.


Genetic variability of Madeira archipelago inferred from Y chromosome, mtDNA and HLA system
A. C. N. Lemos, H. Spinola, R. Gonçalves, A. Fernandes, A. Brehm;
Human Genetic Laboratory, Funchal, Portugal.
Presentation Number: P07.135
The Madeira Archipelago is composed by two inhabited islands, Madeira and Porto Santo. The first settlers of these islands came from north and south of Portugal and Europe (Flandres, France and Italy), jointly with some African slaves.
Three geographic groups were defined within the Archipelago: Funchal (FX), Southwest (SW) and Northeast (NE - including Porto Santo). The Y chromosome haplogroup followed the Y Chromosome Consortium and comparison with both mtDNA and HLA-A, HLA-B and HLA-DRB1 genes was performed. Arlequin was used to compare the three geographic groups within the archipelago and to calculate genetic diversity of Y chromosome SNPs, mtDNA and HLA systems between and within each group.
No significative haplotypic differences were found regarding the Y chromosome SNPs for these three groups, opposite to mtDNA and HLA systems encountered between Southwest and Funchal. We also found major European influence although some African traces are present. The highest level of genetic diversity was found in Funchal for both mtDNA and HLAs.
The aim of this study was to determine the genetic background of the Madeira population, to search for differences within the Archipelago and find out the influence of the colonization in the actual genetic structure of this population.


The coexistence of an East-Asian mitochondrial anthropological marker and the C8270T, A8332C, and A8347C mtDNA mutations in a Hungarian family with dystonia and juvenile stroke syndrome
A. Gal1, K. Pentelenyi1, V. Remenyi1, B. Csanyi2, G. Tomory2, I. Rasko2, M. J. Molnar1,3;
1Department of Neurology, Semmelweis University, Center of Molecular Neurology, Budapest, Hungary, 2Biological Research Center, Szeged, Hungary, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Presentation Number: P05.126
The high variability of the mitochondrial genome contributes to the phenotype of the mtDNA-related disorders. MtDNA mutations have been associated with a variety of clinical manifestations. The 9-bp deletion between mtDNA 8271-8280 was originally thought to be an anthropological marker for peoples of East-Asian origin.
The proband was investigated for marked dystonic features. The clinical symptoms started after a long lasting episode of fever and elevated serum ammonia and lactate level. His brother had transient hyperkinesis, right hemiparesis. Their mother had in her childhood a stroke with aphasia and right hemiparesis. Presently she has moderate truncal ataxia, hypoacusis and cognitive dysfunction.
The mtDNA analysis of the proband found a 9bp deletion “CCCCCTCA” in the mtDNA at the position nt8271-8280, and one C8270T substitution between COII and tRNALys genes in the non-coding hypervariable segment, and two SNPs (A8332G and A8347C) in the tRNALys gene. The C8270T SNP is a pathogenic mutation, the A8332G and A8347C SNPs are not described in the literature. None of the three SNP was found in our 100 control cases. The affected Hungarian family belongs to an ancient B mitochondrial haplogroup.
Conclusion: The B haplogoup and the 9 bp small deletion indicate the east-Asian origin of this family which could be explained by the Hungarian history. The 9 bp deletion may serve as a susceptibility factor for further mtDNA alterations. We assume that the clinical symptoms are related to the pathogenic C8270T mutation and the coexistences of the A8347C and A8332G mutations may modify the clinical symptoms.


Multiple Sclerosis Disease and Mitochondria
M. Houshmand;
NIGEB, Tehran, Iran (Islamic Republic of).
Presentation Number: P05.125
Multiple Sclerosis (MS) is a multifocal demyelinating central nervous system disorder. To assess relationship between mtDNA haplogroups and MS, we have sequenced the mtDNA HVS-I in 54 MS patients and 100 control subjects. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n =10) and control subjects (n =11). The frequencies of the Asian (M, BM) and European (N, J, K) mtDNA haplogroups in five major regions of Iran was investigated. Unexpectedly, the frequencies of the Asian haplogroups M and BM were low in Iran (2.34% for haplogroup M; 17.6% for haplogroup BM and 80.06% for haplogroup N).
We have found that haplogroups A and K are significantly more abundant in MS patients (P=0.042 for haplogroup A and P=0.0005 for haplogroup K). Our findings showed that complex I activities were significantly reduced ( P=0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS. Our data suggest that Iranian tribes probably played a remarkable role in the formation of these ethnic groups. It gives the indication that the haplogroup J may be older than 6000-10000 years, and probably developed in Iran, and then expanded to different regions in Europe and Northwest Asia.


UGT1A genetic polymorphisms in São Miguel population (Azores): implications for pharmacogenetic studies
M. J. Brilhante1, P. R. Pacheco1,2, F. Sigallat1, H. Polena1, R. Cabral1,2, C. C. Branco1,2, L. Mota-Vieira1,2;
1Hospital of Divino Espirito Santo of Ponta Delgada, Azores, Portugal, 2Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Presentation Number: P07.127
UGT enzymes are responsible for glucuronidation and detoxification of endogenous and exogenous compounds. Homozygosity for a polymorphism in the UGT1A1 TATAA box promoter causes Gilbert’s syndrome. This sequence contains six TA repeats (UGT1A1*1), whereas seven repeats (UGT1A1*28) imply reduced gene expression. In UGT1A6, two missense mutations result in three alleles: UGT1A6*1 (T181-R184), UGT1A6*2 (A181-S184) and UGT1A6*3 (T181-S184). UGT1A1*28 and UGT1A6*2 are associated with reduced enzymatic activity.
Here, we determined UGT1A1 and UGT1A6 polymorphisms prevalence in São Miguel population (n=469 healthy individuals), and investigated UGT1A1 association with UGT1A6 polymorphisms. In UGT1A1, we identified five genotypes: 0.4% (TA)5/(TA)6, 50.5% (TA)6/(TA)6, 39.7% (TA)6/(TA)7, 9.2% (TA)7/(TA)7 and 0.2% (TA)6/(TA)8. Five and eight TA repeats are found only in African-ancestry individuals. These alleles confirm our previous results on Sao Miguel genetic ancestry, an admixed population composed of European, Jews and Africans. UGT1A*6 genotype frequencies were 47.5% (*1*1), 36.2%, (*1*2), 7.5% (*2*2), 4.7% (*1*3) and 4.1% (2*3). A strong association between UGT1A1*28 and UGT1A6*2 alleles was observed, since 81.4% homozygous for UGT1A1*28 were also homozygous for UGT1A6*2. Overall, 6.7% were homozygous for both UGT1 polymorphisms, and 39% had at least one variant allele for UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms result in modified expression and activity of UGTs, may influence susceptibility to cancers and predispose to side effects of drugs, such as irinotecan. Currently, we are analyzing three missense mutations in UGT1A7, to evaluate the extension of linkage disequilibrium between UGT1A1, UGT1A6 and UGT1A7. Funded by Azorean Government (M1.2.1./I/003/2005). PRP has PhD grant SFRH/BD/27453/2006.


The 8q24 rs10505470 variant is not associated with prostate cancer risk in patients from the Republic of Macedonia
N. Matevska1, D. Petrovski2, S. Dzikova2, S. Banev2, V. Georgiev2, A. Sikole2, A. J. Dimovski1;
1Faculty of Pharmacy, Skopje, The former Yugoslav Republic of Macedonia, 2Faculty of Medicine, Skopje, The former Yugoslav Republic of Macedonia.
Presentation Number: P04.181
Recent compelling evidence demonstrates chromosome 8q24 as a prostate cancer (PC) susceptibility locus. Multiple variants within three adjacent regions at 8q24 have been identified to impact the risk of PC. Most commonly assessed variants are rs1447295 (region1), rs16901979 (region2) and rs6983267 (region3). Although regions 1 and 3 are close together, they are separated by a recombination hotspot among individuals of European ancestry. Hence, all three neighboring regions seem to contribute independently to the PC risk, and the combined effects of SNPs across regions follow a multiplicative model. In order to examine the association between the PC risk and all three regions of 8q24 we designed a case-control study of randomly selected PC patients and controls without history of any malignant disease. Herein, we present the results of the association of PC risk and rs10505470 variant which is known to be in strong LD with rs6983267 in region 3. The rs10505470 genotypes were determined using custom designed TaqMan SNP genotyping assay on a Real-time PCR analyzer (MxPro 3005P). We did not observe a difference in overall allelic frequencies and genotype distribution {(A allele 0.518 for patients; 0.516 for controls); (AA 28.24%, AG 47.06%, GG 24.71% for patients; AA 27.60%, AG 47.92%, GG 24.48% for controls)}. Furthermore there was no significant difference after stratification of patients in subgroups according to age and Gleason score. Our findings led us to conclude that rs10505470 variant is not implicated with PC risk, time of onset or PC aggressiveness in Macedonian population.


Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population
H. Kokotas1, L. Van Laer2, M. Grigoriadou1, V. Iliadou3, J. Economides4, S. Pomoni1, A. Pampanos1, N. Eleftheriades5, E. Ferekidou6, S. Korres6, A. Giannoulia-Karantana7, G. Van Camp2, M. B. Petersen1;
1Institute of Child Health, Athens, Greece, 2University of Antwerp, Antwerp, Belgium, 3AHEPA Hospital, Thessaloniki, Greece, 4‘Aghia Sophia’ Children’s Hospital, Athens, Greece, 5St. Loukas Hospital, Thessaloniki, Greece, 6Athens University, Athens, Greece, 7Athens University Medical School, Athens, Greece.
Presentation Number: P06.080
Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to forty percent of autosomal recessive, congenital, severe to profound hearing impairment cases result from mutations in a single gene, GJB2. The 35delG mutation accounts for the majority of GJB2 mutations detected in Caucasian populations and represents one of the most frequent disease mutations identified so far. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, whilst other studies support the theory of a common founder. Greece is amongst the countries presenting high frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers, mapping within or flanking the GJB2 gene, as compared to 60 Greek hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene, at distances of 34 kb on the centromeric and 90 kb on the telomeric side of the gene, respectively. Our study supports the hypothesis of a founder effect and we further propose that ethnic groups of Greek ancestry could have propagated the 35delG mutation, as evidenced by historical data beginning from the 15th century BC.


Variants in the Vitamin D Receptor Gene and Melanoma Etiology
L. P. Fernandez1, E. Barroso1, R. L. Milne1, G. Pita1, M. Tanic1, J. A. Aviles2, P. Lazaro2, J. Benitez1, G. Ribas1;
1Spanish National Cancer Research Centre (CNIO), Madrid, Spain, 2Hospital Gregorio Marañon, Madrid, Spain.
Presentation Number: P07.086
The aetiology of malignant melanoma (MM) remains unclear but it is known that both genetic and environmental factors influence the development of sporadic disease. The main reason for the increasing incidence of MM in the general population is greater sun exposure. Epidemiologic studies confirm that UV radiation is the main factor involved in the pathogenesis of the disease. Among phenotypic factors, fair pigmentation and low tanning ability are the most important risk factors. In recent years there has been a increasing interest in the role of vitamin D and its active metabolites in MM susceptibility. Sunlight induces production of vitamin D that has been associated with antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma cells mediated through the vitamin D receptor. In this study we explore the interaction between sunlight exposure and vitamin D receptor gene polymorphisms in the etiology of MM.
This case-control study included 131 consecutive Spanish MM patients from the Dermatology Unit of the Gregorio Marañón Hospital and 245 control subjects frequency matched for sex and age. Phenotypic information was collected using a standardized questionnaire.
Four SNPs in the vitamin D receptor gene (VDR) were genotyped. SNPs on exons or in the putative promoter region were selected. We were able to identify several individual SNPs and haplotypes associated with tumoral characteristics such as breslow index and melanoma location. We also discuss the role of VDR variants as possible markers for MM and its agresiveness.


Natural Background Radiation Dictates Extensive Structural Polymorphism in the Human Y-Chromosome
S. Premi, J. Srivastava, S. Ali;
National Institute of Immunology, Delhi, India.
Presentation Number: P07.029
Ionizing radiations are known to affect the human genome but its impact on human Y chromosome still remains unaddressed. Here we analyze 300 males residing in an area containing the world’s highest level of natural background radiation (NBR) and 390 controls from different parts of India. Random microdeletions were observed in 95% of the NBR exposed males with higher frequency in AZFc region but without gr/gr or b2/b4 phenotypes. Scrutiny of the male fertility associated genes showed copy number polymorphism (CNP) and tandem duplication in 84%, and exclusive deletion of DBY in 25% of the exposed males. Detailed analysis revealed multiple polymorphic copies of SRY and CDY1 genes in addition to several known and novel mutations of the SRY gene. Amongst NBR exposed males with multiples copies of the DAZ genes, 75% showed varying FISH signals for DAZ genes with unilocus or bilocus duplications whereas 30% showed mosaicism in terms of presence/absence of the signals in 6-8% cells and unexpected number of signals in 9-12% interphase nuclei. Interestingly, all these alterations were exclusively somatic in nature substantiating normal fertility status of NBR exposed males. Though the actual mechanism is not known, we hypothesize that some putative innate protective mechanisms are operative in germline to counteract the effect of NBR. Analysis of additional Y linked loci may uncover the overall impact of NBR on the structural and functional attributes of this chromosome.


Persons with greater individual genome-wide heterozygosity show lower increase of cortisol levels during acute psychological stress
L. Zgaga1, C. Hayward2, Z. Biloglav1, I. Kolcic1, O. Polasek1,3, D. Rudan4, A. Vorko-Jovic1, A. Wright2, H. Campbell3, I. Rudan3;
1Medical School, University of Zagreb, Zagreb, Croatia, 2MRC Human Genetics Unit, Edinburgh, United Kingdom, 3Faculty of Medicine, Edinburgh, United Kingdom, 4Dubrava University Hospital, Zagreb, Croatia.
Presentation Number: P07.061
Aim: Genome-wide heterozygosity (GWH) was reported to affect a range of quantitative traits in humans, animals and plants. Several studies suggested that the underlying mechanism is increased compensation potential to environmental stressors in outbred individuals. In humans, psychological stress has been consistently linked to an increase in cortisol levels, which eventually impairs immune system function. We studied whether GWH status affects the increase in cortisol levels in persons reporting acute psychological stress.
Materials and methods: We studied 1,026 examinees from the Vis island, Croatia. Standardised multilocus heterozygosity (sMLH) was computed for each person from a genome-wide scan using 317.000 single nucleotide polymorphisms. Morning cortisol level was measured from the blood in all participants. Reported acute psychological stress was measured using General Health Questionnaire 30 (GHQ-30).
Results: GHQ-30 scores had a significant effect on the increase of cortisol (p<0.001). All examinees were therefore categorized in 3 groups according to the increasing levels of reported psychological stress within GHQ-30. In all groups, the effect of sMLH on cortisol levels was investigated using general linear model with inclusion of potential confounding variables. In the group reporting mild stress the effect was weak and non-significant (Beta=-0.058, p=0.34), but with increase of reported stress levels to moderate and strong, the effect became larger and statistically significant (Beta =-0.125, p=0.003; and Beta=-0.188, p=0.04, respectively).
Conclusion: This study implies that, in humans, the increase in individual GWH may buffer the effects of psychological stress on cortisol levels, thus protecting the physiological function of immune and endocrine system.


Comparison of genome-wide homozygosity-by-descent estimates in human isolated population
O. Polasek1,2, I. Kolc(ic'2, L. Zgaga2, Z. Biloglav2, A. Vorko Jovic'2, D. Rudan3, I. Rudan4, A. Wright5, H. Campbell1, A. Leutenegger6,7;
1Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom, 2Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia, 3Clinical Hospital Dubrava, Zagreb, Croatia, 4Centre for Global Health, University of Split, Split, Croatia, 5Human Genetics Unit, Medical Research Council, Edinburgh, United Kingdom, 6Inserm U535, Villejuif, France, 7Univ. Paris-Sud, Villejuif, France.
Presentation Number: P07.068
The aim of this study was to investigate several methods of marker based genome-wide homozygosity estimation. The study sample consisted of 118 members of a single extended family living on the Adriatic Croatian island of Vis, where no pedigree based inbreeding was observed, and therefore no homozygosity by descent, HBD, was expected. Individuals were genotyped for 810 microsatellite markers and a 317k Illumina chip. Five approaches were compared: the proportion of heterozygous loci (multilocus heterozygosity, MLH), two methods of moments approaches that use different weighting approaches (ADC and PLINK), and finally 2 maximum likelihood approaches, one singlepoint and the other multipoint, using a hidden Markov model for marker dependencies (FEstim). The latter is the only existing multipoint method for HBD estimation and gives estimates the closest to the true HBD values, as shown previously in a simulation study. The results indicated that the two methods of moments approaches correlated highly with MLH and hence did not bring much information about HBD. On the other hand, the two maximum likelihood approaches exhibited zero value estimates when homozygosity was likely due to chance. A total of 68 individuals (57.6%) had no HBD as defined by the FEstim, while a total of 4 individuals (3.9%) had FEstim values over 0.0625 indicating inbreeding closer than first cousins. These methods can be used to differentiate homozygosity by chance vs. HBD, which may be important in investigation of the genome-wide heterozygosity effects on quantitative and health related traits.


Genetic differentiation of ethnic groups of Russia evaluated by genes of hereditary disorders
R. A. Zinchenko, V. A. Galkina, E. K. Ginter;
Research Center for Medical Genetics, ??scow, Russian Federation.
Presentation Number: P07.057
On the basis of genetic epidemiological study the prevalence of autosomal dominant, autosomal recessive and X-linked recessive disorders in 10 regions of Russia (5 ethnic groups: Russians, Maris, Chuvashs, Udmurts, Adighes) was estimated. The size of the investigated population was more than 2.5 millions of persons. Genetic differentiation between populations of different hierarchical levels by estimated loads of hereditary diseases was established. The prevalence rate of all Mendelian disorders varied in the investigated populations from 1.34 to 5.92 per 1000 persons. Genetic diversity of hereditary diseases in the investigated populations was also under our study. 199 autosomal dominant, 165 autosomal recessive and 48 X-linked recessive diseases were revealed. Most of them were rare or very rare. There were some cases of local accumulations of hereditary disorders in the investigated populations. Simultaneously with medical genetic study the population genetic study was performed in the populations. By comparing both studies it was suggested that the genetic drift is a most important factor which determines genetic differentiation of populations by the prevalence and genetic diversity of autosomal disorders.


Genetic care of families affected by albinism in an African cultural context
P. M. Lund;
Coventry University, Coventry, United Kingdom.
Presentation Number: P09.47
The birth of a baby with the autosomal recessive condition oculocutaneous albinism (OCA) in a black African population is often traumatic for the mother as the phenotype, with hypopigmentation of the hair, skin and eyes, differs so visibly from the normal level of pigmentation in this group. The incidence of OCA among the Venda of northern South Africa is relatively high, with 1 in 1970 affected, giving a carrier rate of 1 in 23. Myth and superstition surround OCA, with affected families believing they have been bewitched. The experiences of genetic nurses at the large regional hospitals in Venda and of families who have benefited from their genetic counselling services are explored via semi structured interviews. The genetic nurses, based in the midwifery section, identify affected babies as part of the National Birth Surveillance Programme and intervene immediately to inform the mother of the special health care needs of her baby. They explain the genetic causes of OCA and aim to empower her to counter negative attitudes she is likely to encounter from her family, who may accuse her of infidelity, and the wider community when returning to her rural home. Barriers to the provision of genetic care in this remote, rural region and strategies adopted by health care professionals to overcome these difficulties are explored. This genetic practice is a model for providing care to those affected by genetic conditions in rural, low resources regions of the world.


MC1R polymorphisms, phenotype and UVB radiation sensitivity in melanoma risk patients
P. Aguilera1, C. Carrera1, G. Salerni1, F. Cuellar1, Z. Ogbah2, J. A. Puig-Butille2, M. Lecha3, J. Malvehy1, S. Puig1;
1Melanoma Unit, Barcelona, Spain, 2Melanoma Unit, Genetic Service, Barcelona, Spain, 3Photobiology and Phototherapy Unit, Dermatology Service, Barcelona, Spain.
Presentation Number: P04.161
Background: UV radiation (UVR) plays an important role in melanocytic tumours development. History of intense intermittent sun-exposure, phenotypic characteristics encoding melanocortin-1 receptor gene (MC1R) and the presence of multiple nevi are risk markers to develop malignant melanoma. Familiar melanoma represents 10% of all melanomas and it is supposed that genetic burden in these patients plays a more important role than environmental factors.
Objective: to study in different melanoma-risk patient settings the association between phenotypic characteristics, number of nevi, UVR sensitivity and polymorphisms in MC1R.
Methods: two groups of high risk melanoma patients were studied (N=32):
Group 1: Dysplastic nevus syndrome (DNS) patients (N=23).
Group 2: Melanoma patients belonging to familial melanoma (N=9).
UVB sensitivity, phenotypic and genotypic characterization were performed.
Results: patients from DNS had a higher UV-B photosensitivity (reduced UV-B minimal erythemal dose) compared with patients from familiar melanoma group (mean 88mJ/cm2± 26 vs 122 mJ/cm2 ± 26; p<0,005). In both groups a high percentage of MC1R polymorphisms were detected (at least 1 polymorphism in 75% of patients in group 1 vs 78% in group 2). However, a different percentage of red hair type polymorphisms (RHP) was observed in the 2 groups (20% in group 1 vs 66% in group 2, p<0,01).
Conclusions: Patients affected by DNS presented high UV-B sensitivity, similar to North European populations or patients with photo-dermatoses. Similar percentage of MC1R polymorphisms were detected in our both samples, however, RHPs were strongly associated with familial melanoma, an unexpected result in our Mediterranean area.


Super-hotspots for Meiotic Recombination in the Human Genome
Presentation Time: Tuesday, 11:00 a.m. - 11:15 a.m.
I. L. Berg, A. J. Webb, A. J. Jeffreys;
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
Presentation Number: C13.2
Homologous recombination is a vital process for ensuring proper chromosome segregation during meiosis, as well as increasing diversity by reshuffling haplotypes between generations. In this study, we analysed Phase II HapMap data to identify autosomal regions showing extreme breakdown of linkage disequilibrium (LD). Sixteen of these regions were selected for crossover analysis directly in sperm. All contained active sperm hotspots, with similar characteristics as at previously studied hotspots, i.e. normally-distributed crossover breakpoints within regions 1-2 kb wide. These new hotspots were on average 10 fold more active than previously characterised autosomal hotspots and include the most active crossover hotspots yet discovered in the human genome. Their activity is however poorly predicted from LD data. Most crossovers in these hotspots were simple, exchanging haplotypes within a single interval between markers. However, 0.3% of exchanges were more complex, switching haplotypes at several intervals during an exchange event. Most of these occurred within the boundaries of the hotspot while 22% occurred beyond the hotpot, implying a broader region involved during intermediate stages of recombination. Several hotspots showed crossover frequency variation between men, including two cases of complete presence/absence polymorphism. Instances of extreme or subtle biased gene conversion accompanying crossover were observed within some hotspots, in some cases correlating with crossover frequency variation between men. Curiously none of the most active hotpots showed polymorphism or strongly biased conversion, in contrast to the prediction that these hotpots should be the most vulnerable to attenuation/extinction by meiotic drive in favour of recombination suppressors.


G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth
Presentation Time: Saturday, 7:00 p.m. - 7:15 p.m.
S. M. Pasternack1, I. von Kügelgen2, K. Al Aboud3, Y. Lee4,5, F. Rüschendorf5, K. Voss6, A. M. Hillmer7, G. J. Molderings2, T. Franz8, A. Ramirez9,10, P. Nürnberg10,11, M. M. Nöthen1,7, R. C. Betz1;
1Institute of Human Genetics, Bonn, Germany, 2Department of Pharmacology, Bonn, Germany, 3Department of Dermatology, Makkah, Saudi Arabia, 4Department of Pediatric Pneumology and Immunology, Berlin, Germany, 5Max Delbrück Center for Molecular Medicine, Berlin, Germany, 6Department of Human Genetics, Würzburg, Germany, 7Department of Genomics, Bonn, Germany, 8Department of Anatomy, Bonn, Germany, 9Institute of Human Genetics, Cologne, Germany, 10Center for Molecular Medicine Cologne, Cologne, Germany, 11Cologne Center for Genomics, Cologne, Germany.
Presentation Number: PL2.3
Hypotrichosis simplex (MIM 146520 and MIM 605389) is a group of hereditary non-syndromic human alopecias that affects men and women equally. The hair loss is diffuse and progressive, and usually begins in early childhood. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, a gene which encodes an orphan G protein-coupled receptor. We analysed expression-patterns of P2RY5 in various human and mouse tissues and performed western blot and immunofluorescence analyses to characterize the protein. Furthermore, we identified oleoyl-L-a-lysophosphatidic acid (LPA), a bioactive lipid, as being a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signalling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. As P2RY5 is expressed in human hair follicle cells, but LPA4 and LPA5 are not, a loss of P2Y5 function will not be compensated for, and will ultimately lead to pathological changes and hair loss.
Our study is the first to implicate a G protein-coupled receptor as being essential for and specific to the maintenance of human hair growth. With the functional characterization of the P2Y5 receptor, we identify the missing link which is required for the transmission of the LPA signal through the cell membrane in hair follicle cells. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans.