Ancient origin of the CAG expansion causing Huntington disease in a Spanish population

25 p. Figuras, tablas, bibliografíaHuntington disease (HD, MIM# 143100) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (2 mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCGrs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking STRs D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.This work was supported by the Fondo de investigación Sanitaria (FIS grant 01/1159), the Instituto de Salud Carlos III (grant G03/56) for the Spanish Network on Cerebellar Ataxias, and the Generalitat Valenciana (grant GRUPOS03/015).Peer reviewe

Ancient origin of the CAG expansion causing Huntingtons disease in a Spanish population.

[EN] Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, in Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (two mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCG-rs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking short tandem repeats (STRs) D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.We are grateful for the kind collaboration of patients and families. This work was supported by the Fondo de investigación Sanitaria (FIS grant 01/1159), the Instituto de Salud Carlos III (grant G03/56) for the Spanish Network on Cerebellar Ataxias, and the Generalitat Valenciana (grant GRUPOS03/015).García-Planells, J.; Burguera, JA.; Solís, P.; Millán, JM.; Ginestar Peiro, D.; Palau, F.; Espinós-Armero, CÁ. (2005). Ancient origin of the CAG expansion causing Huntingtons disease in a Spanish population. Human Mutation. 25(5):453-459. https://doi.org/10.1002/humu.2016745345925

Huntington’s disease in Finland. Epidemiologic, genetic and clinical studies

Huntington’s disease (HD) is a lethal, dominantly inherited neurodegenerative disorder reported to be unusually rare in Finland. The overall HD prevalence and the proportion of late-onset cases (LOHD) are increasing in many populations. The characteristics of LOHD are nevertheless poorly understood. Information on neurological comorbidity in patients with HD is also scarce. These retrospective studies analyzed a national Finnish HD cohort in the time frame 1987-2010 by searching national registries and archives. Data was extracted from medical records. Population genotypes were obtained from the 1000 Genomes project. The prevalence of HD in Finland was found to be 2.12/100,000, or over four times more common than reported previously. Nonetheless, HD is more uncommon than in other Western European countries. The national cohort of 207 patients included 52 (25%) patients with LOHD; they had poorer motor status at the time of diagnosis than patients with mid-age onset, possibly because of the diagnostic delay. No other differences were detected between these groups. Interestingly, only one individual (0.5% of all HD patients in Finland) with juvenile-onset HD was identified. The length of the affected CAG repeat or its intergenerational stability did not differ from those reported in other populations. However, the high risk chromosome 4 haplogroup A was relatively uncommon in the Finnish general population (39.2%), possibly partly explaining the relative rarity of HD in Finland. Patients with adult-onset HD had epilepsy and strokes as often as reported in the general population. HD patients were, however, at an increased risk of suffering subdural haematomas.Huntingtonin tauti Suomessa. Epidemiologisia, perinnöllisyystieteellisiä ja kliinisiä tutkimuksia. Huntingtonin tauti (HD) on autosomaalisesti vallitsevasti periytyvä, kuolemaan johtava hermoston rappeumasairaus. Taudin on todettu olevan poikkeuksellisen harvinainen Suomessa. Monissa väestöissä HD:n esiintyvyyden sekä myöhäisiällä alkavan HD:n (LOHD) osuuden on havaittu lisääntyneen. LOHD:n ominaispiirteet tunnetaan kuitenkin huonosti. Myös HD-potilaiden neurologisesta oheissairastavuudesta on käytettävissä vain hyvin vähän tietoja. Näissä takautuvissa tutkimuksissa analysoitiin kansallinen suomalainen HD-potilaiden kohortti vuosilta 1987-2010. Potilaat tunnistettiin kansallisista rekistereistä sekä tietyistä arkistoista. Tutkimustiedot kerättiin sairauskertomuksista. Väestön genotyyppitiedot saatiin 1000 Genomes –projektista. Huntingtonin taudin vallitsevuuden (2,12/100’000) havaittiin olevan Suomessa yli nelinkertainen aiempaan tutkimustietoon nähden. Silti HD on selvästi harvinaisempi Suomessa kuin muissa läntisen Euroopan maissa. Kansallisesta 207 HD-potilaan kohortista 52 (25%) oli LOHD-potilaita ja heidän motoriset oireensa ja löydöksensä olivat diagnoosinteon hetkellä vaikeampia kuin aiemmalla aikuisiällä sairastuneiden, mikä mahdollisesti johtui diagnoosien viivästymisestä LOHD-potilailla. Muuten näiden ryhmien välillä ei havaittu eroja. Yllättäen löysimme vain yhden (0,5%) potilaan, jolla HD alkoi nuoruusiällä. Tautialleelin CAG-toistojakson pituus tai sen sukupolvien välinen vakaus eivät eronneet muissa väestöissä raportoiduista. Kromosomin 4 korkean riskin haploryhmä A:n havaittiin kuitenkin olevan suomalaisessa väestössä verrattain harvinainen (39,2%), mikä saattaa osittain selittää HD:n suhteellista harvinaisuutta Suomessa. Aikuisiällä HD-diagnoosin saaneilla potilailla oli epilepsiaa ja aivoverenkiertohäiriöitä samassa määrin kuin valtaväestöllä. Kovakalvon alaisten verenvuotojen riski havaittiin HD-potilailla suurentuneeksi.Siirretty Doriast

Trinucleotide repeat scanning in portuguese familial amyloidotic polyneuropathy kindreds exhibiting genetic anticipation

Dissertação de Mestrado apresentada à Faculdade de Medicina da Universidade do Port

Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.

This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden. The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups. Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants. These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained by combinations of rare variants with relatively large effect size, such as PINK1 G411S

Essentially yours: the protection of human genetic information in Australia

ALRC Report 96 (tabled May 2003)  was the product of a two-year inquiry by the ALRC and the Australian Health Ethics Committee (AHEC) of the NHMRC, involving extensive research and widespread public consultation.The inquiry was the most comprehensive ever undertaken into these issues in Australia or overseas. The report covers an extensive range of activities in which genetic information plays—or soon will play—an important role. The two-volume, 1200 page report makes 144 recommendations about how Australia should deal with the ethical, legal and social implications of the New Genetics. This Report reflects the law as at 14 March 2003

Laktaasinpuutosten molekyyligenetiikka

Congenital lactase deficiency (CLD) (MIM 223000) is a rare autosomal recessive gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. The CLD locus was previously assigned by linkage and linkage disequilibrium analyses on 2q21 in 19 Finnish families. In this study, the molecular background of this disorder is reported. The CLD locus was refined in 32 CLD patients in 24 families by using microsatellite and single nucleotide polymorphism (SNP) haplotypes. Mutation analyses were performed by direct sequencing. We identified 5 distinct mutations in the lactase (LCT) gene, encoding the enzyme that hydrolyzes lactose in the intestinal lumen. These findings facilitate genetic testing of CLD in clinical practice and enable genetic counseling. The present data also provide the basis for detailed characterization of the molecular pathogenesis of this disorder. Adult-type hypolactasia (MIM 223100) (lactase non-persistence, lactose intolerance) is an autosomal recessive gastrointestinal condition that is a result of a decline in the activity of lactase in the intestinal lumen after weaning. Adult-type hypolactasia is considered to be a normal phenomenon among mammals and symptoms are remarkably milder than experienced in CLD. Recently, a variant C/T-13910 was shown to associate with the adult-type hypolactasia trait, locating 13.9 kb upstream of the LCT gene. In this study, the functional significance of the C/T-13910 variant was determined by studying the LCT mRNA levels in intestinal biopsy samples in children and adults with different genotypes. RT-PCR followed by solid-phase minisequencing was applied to determine the relative expression levels of the LCT alleles using an informative SNP located in exon 1. In children, the C-13910 allele was observed to be downregulated after five years of age in parallel with lactase enzyme activity. The expression of the LCT mRNA in the intestinal mucosa in individuals with the T-13910 A-22018 alleles was 11.5 times higher than that found in individuals with the C-13910, G-22018 alleles. These findings suggest that the C/T-13910 associated with adult-type hypolactasia is associated with the transcriptional regulation of the LCT gene. The presence of the T-13910 A-22018 allele also showed significant elevation lactase activity. Galactose, the hydrolysing product of the milk sugar lactose, has been hypothesized to be poisonous to ovarian epithelial cells. Hence, consumption of dairy products and lactase persistence has been proposed to be a risk factor for ovarian carcinoma. To investigate whether lactase persistence is related to the risk of ovarian carcinoma the C/T-13910 genotype was determined in a cohort of 782 women with ovarian carcinoma 1331 individuals serving as controls. Lactase persistence did not associate significantly with the risk for ovarian carcinoma in the Finnish, in the Polish or in the Swedish populations. The findings do not support the hypothesis that lactase persistence increases the risk for ovarian carcinoma.Synnynnäinen laktaasin puutos (congenital lactase deficiency, CLD [MIM 223000]) on vakava peittyvästi periytyvä suolistosairaus. Potilailla on tyypillistä runsas vetinen ripuli, joka ilmenee maitoruokinnan alettua. Ripuli johtaa ravintoaineiden imeytymishäiriöön ja kasvun hidastumiseen. Potilaiden laktaasiaktiivisuus on havaittu ohutsuolessa hyvin alhaiseksi. Vaikea ripuli johtuu nimenomaan hydrolysoimattoman laktoosin kertymisestä suolistoon aiheuttaen osmoosin, vaikean kuivumistilan, asidoosin ja painon menetyksen syntymäpainon alapuolelle. Laktoositon ruokavalio poistaa oireet ja palauttaa kehityksen normaaliksi. CLD-vauvoja syntyy Suomessa yksi vuodessa (1:60000). Se kuuluu yhdessä 36 muun harvinaisen Suomessa esiintyvän sairauden kanssa ns. suomalaiseen tautiperintöön. Tutkimuksen tarkoituksena oli tunnistaa CLD:lle altistavat geneettiset tekijät geenien kartoitus- ja sekvensointimenetelmien avulla. Tutkimuksessa analysoitiin 32 CLD-potilasta 24 eri perheestä. Löysimme viisi CLD:lle altistavaa mutaatiota laktaasigeenistä (LCT), joista Y1390X-mutaation havaittiin olevan yleisin ns. Finmajor-mutaatio. Löydökset mahdollistavat sairauden perinnöllisen testauksen ja neuvonnan. Lapsuuden jälkeen tai nuorella aikuisiällä havaittu primääri maitosokerin imeytymishäiriö (MIM 223100) (tunnettu myös laktoosi-intoleranssina) on yleinen laktaasin aktiivisuuden alenemisesta johtuva ilmiö. Laktaasiaktiivisuus alenee suolistossa 5-10% lapsuudesta havaitusta ja laktoosi ruokavaliossa aiheuttaa suolistoperäisiä oireita. Laktaasin puutos on nisäkkäille luonnollinen ilmiö, näin lapsi vierotetaan rinnasta käyttämään kiinteätä ravintoa. Kuitenkin joillain ihmisillä korkea laktaasiaktivisuus säilyy koko elinajan. Kyseiseen ilmiasuun on havaittu liittyvän yhden emäksen muutos C→T-13910 noin 14 kiloemästä laktaasigeenistä ylävirtaan. T-13910-muutoksen perineet henkilöt säilyttävät laktaasiaktiivisuuden ja kyvyn pilkkoa laktoosia. Tämän tutkimuksen tarkoituksena oli määrittää C/T-13910 emäsmuutoksen vaikutus laktaasigeenin ilmentymiseen lähetti-RNA tasolla lapsilla ja aikuisilla. Laktaasigeenin ilmentymistä tutkittiin geenispesifisellä minisekvensointimenetelmällä pohjukaissuolesta otetuista näytteistä. Havaitsimme, että laktaasia säädellään transkriptiotasolla, C-13910-muutos sallii laktaasigeenin lähetti-RNA:n laskun. Ilmiö oli havaittavissa lapsilla viiden ikävuoden jälkeen. Aikuisilla T-13910-emäsmuutos vastasi 92% havaitusta laktaasigeenin lähetti-RNA:n ilmentymisestä, joka näkyi myös korkeana laktaasiaktiivisuutena. Galaktoosi on glukoosin ohella laktoosin hajoamistuote. Galaktoosin on havaittu eläinkokeissa olevan myrkyllinen munasarjojen epiteelisoluille ja sen on epäilty aiheuttavan munasarjasyöpää. Tästä syystä korkean laktaasiaktiivisuuden ja maitotuotteiden runsaan nauttimisen on oletettu nostavan munasarjasyövän riskiä. Tässä tutkimuksessa määritettiin 782 suomalaisen, puolalaisen ja ruotsalaisen munasarjasyöpäpotilaan ja 1331 verrokkinäytteen C/T-13910-genotyyppi tutkiaksemme onko korkealla laktaasiaktiivisuudella yhteyttä syövän syntyyn. Genotyypillä ei havaittu olevan vaikutusta syöpäriskiin tutkituissa väestöryhmissä. Jatkotutkimuksella pyritään selvittämään maitotuotteiden kulutuksen merkitystä munasarjasyöpään eri C/T-13910 genotyypeillä