Publications by authors named "Kirsi Huoponen"

24 Publications

  • Page 1 of 1

Genomic analysis of the 55 kDa subunit of DNA polymerase epsilon in human intracranial neoplasms.

Cancer Genomics Proteomics 2010 May-Jun;7(3):143-6

Department of Pathology, University of Turku, FIN-20520 Turku, Finland.

Background: Defects of some DNA polymerases have shown cancer associations, but there are only limited data on DNA polymerase (Pol) epsilon.

Materials And Methods: We examined 26 human brain neoplasm DNA samples and 8 control blood samples (from Poland) for possible mutations in the entire coding region of the 55 kDa small subunit of human DNA Pol epsilon gene using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis, and sequence analysis of DNA.

Results: One single base intronic transition in intron 14 was found. The AATT deletion previously found in some breast and colorectal tumors was not found in samples from brain neoplasms or controls, but it was found in 1/100 normal blood samples from South-West Finland.

Conclusion: We found no evidence that potential mutations in the 55 kDa subunit of DNA Pol epsilon are a contributing factor in the development of the tested cases of human intracranial tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2010

A familial CHARGE syndrome with a CHD7 nonsense mutation and new clinical features.

Clin Dysmorphol 2008 Oct;17(4):249-53

The Department of Medical Genetics, University of Turku, Turku, Finland.

The autosomal dominant CHARGE syndrome (MIM musical sharp214800) is caused by mutations in the CHD7 gene. It is usually sporadic but a few cases with gonadal mosaicism and familial inheritance have been reported. We describe a familial CHARGE syndrome in a two-generation Finnish family with a nonsense mutation in the CHD7 gene. Detailed clinical examination of the affected family members was performed, and mutations in the CHD7 gene were analysed with direct sequencing and multiplex ligation-dependent probe amplification. A nonsense mutation, p.Q1599X, was detected in exon 21 of the CHD7 gene in three affected family members. The father was only mildly affected, whereas his son had a very severe manifestation of the syndrome, causing death at the age of 3 months. The second pregnancy was prematurely terminated in the 23rd week because of cardiac anomalies detected in the ultrasound scan. The father's brother also had mild symptoms, but no mutation was detected in him. In this report, the variability of clinical symptoms within families and the clinical importance of mildly affected patients with the CHARGE syndrome are underlined with implications for molecular genetic diagnostics of the syndrome. Features not described in the CHARGE syndrome before are also presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCD.0b013e328306a704DOI Listing
October 2008

Carnitine deficiency and L-carnitine supplementation in lysinuric protein intolerance.

Metabolism 2008 Apr;57(4):549-54

Department of Pediatrics, University of Turku, 20520 Turku, Finland.

The aim of the study was to investigate the prevalence and mechanisms of development of carnitine deficiency in patients with lysinuric protein intolerance (LPI). In our cohort of 37 Finnish patients with LPI, 8 (8-52 years of age) have been diagnosed with hypocarnitinemia. Their free and total serum carnitine levels, acyl carnitine profiles, renal function, diet, and medication were compared with the data from 8 age- and sex-matched patients with LPI not treated with carnitine supplementation. In patients with LPI, hypocarnitinemia was strongly associated with female sex, renal insufficiency, and the use of ammonia-scavenging drugs. Of the 8 hypocarnitinemic patients, 3 complained of muscle weakness, and their symptoms disappeared during carnitine supplementation. Oral lysine supplementation did not correct hypocarnitinemia in our patients. The patients with LPI are at considerable risk for carnitine deficiency. Supplementation of hypocarnitinemic LPI patients with oral L-carnitine improved serum total carnitine values, but the ratio of free and total carnitine remained subnormal in all supplemented patients except one. Furthermore, decreased ratio of free and total serum carnitine was common even in LPI patients with normal total serum carnitine concentration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2007.11.019DOI Listing
April 2008

Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions.

Genet Med 2007 Oct;9(10):690-4

Department of Medical Genetics, University of Turku, Turku, Finland.

Purpose: Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German patients referred for molecular confirmation of the clinical diagnosis of suspected CHARGE syndrome.

Methods: Quantitative real-time polymerase chain reaction or multiplex ligation-dependent probe amplification assays did not reveal deletions in mutation negative cases, suggesting that larger CHD7 deletions are not a major cause of CHARGE syndrome.

Results: In this group of 74 patients, we found mutations in 30 cases. 22 mutations were novel, including 11 frameshift, 5 nonsense, 3 splice-site, and 3 missense mutations. One de novo frameshift mutation was found in the last exon and is expected to result in a minimally shortened CHD7 polypeptide. Because the mutation is associated with a typical CHARGE syndrome phenotype, it may indicate the presence of an as yet unknown functional domain in the very carboxyterminal end of CHD7.

Conclusions: Our mutation detection rate of 40.5% is reflective of screening an unselected sample population referred for CHD7 testing based on suspected clinical diagnosis of CHARGE syndrome and not for having met strict clinical criteria for this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/gim.0b013e318156e68eDOI Listing
October 2007

Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.

Am J Hum Genet 2007 Aug 4;81(2):228-33. Epub 2007 Jun 4.

Mitochondrial Research Group, Department of Ophthalmology and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/519394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950812PMC
August 2007

First reported case of lysinuric protein intolerance (LPI) in Lithuania, confirmed biochemically and by DNA analysis.

J Appl Genet 2007 ;48(3):277-80

Department of Human and Medical Genetics, Vilnius University, Vilnius, Santariskiu 2, Lithuania.

We report on an 18-year-old Lithuanian girl with hepatosplenomegaly noticed at birth, which progressed thereafter. The patient had to wait about 17 years for an accurate diagnosis and appropriate therapy. Lactase deficiency, congenital cataract of the right eye, and osteoporosis were observed. Episodes of drowsiness were caused by intake of high-protein food. Laboratory findings included slight hyperammonaemia, high plasma Citr, Ala, Gly, Glu, Ser levels, as well as citrullinuria, lysinuria, glutaminuria, alaninuria, argininuria, prolinuria, hydroxyprolinuria, ornithinuria, and orotic aciduria. Aversion to high-protein diet strongly suggested a disorder resulting in hyperammonaemia. Citrullinaemia was suspected. Subsequently the diagnosis of LPI was made on the basis of biochemical and clinical features. Molecular genetic testing revealed a mutation in the SLC7A7 gene, confirming the diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/BF03195224DOI Listing
October 2007

Heterodimerization of y(+)LAT-1 and 4F2hc visualized by acceptor photobleaching FRET microscopy.

Biochim Biophys Acta 2007 Oct 3;1768(10):2345-54. Epub 2007 May 3.

Department of Medical Genetics, University of Turku, Turku, Finland; Turku Centre for Biotechnology, University of Turku, Biocity, Turku, Finland.

y(+)LAT-1 and 4F2hc are the subunits of a transporter complex for cationic amino acids, located mainly in the basolateral plasma membrane of epithelial cells in the small intestine and renal tubules. Mutations in y(+)LAT-1 impair the transport function of this complex and cause a selective aminoaciduria, lysinuric protein intolerance (LPI, OMIM #222700), associated with severe, complex clinical symptoms. The subunits of an active transporter co-localize in the plasma membrane, but the exact process of dimerization is unclear since direct evidence for the assembly of this transporter in intact human cells has not been available. In this study, we used fluorescence resonance energy transfer (FRET) microscopy to investigate the interactions of y(+)LAT-1 and 4F2hc in HEK293 cells expressing y(+)LAT-1 and 4F2hc fused with ECFP or EYFP. FRET was quantified by measuring fluorescence intensity changes in the donor fluorophore (ECFP) after the photobleaching of the acceptor (EYFP). Increased donor fluorescence could be detected throughout the cell, from the endoplasmic reticulum and Golgi complex to the plasma membrane. Therefore, our data prove the interaction of y(+)LAT-1 and 4F2hc prior to the plasma membrane and thus provide evidence for 4F2hc functioning as a chaperone in assisting the transport of y(+)LAT-1 to the plasma membrane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamem.2007.04.020DOI Listing
October 2007

Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance.

J Pediatr 2007 Jun;150(6):631-4, 634.e1

Department of Pediatrics, University of Turku, Turku, Finland.

Objective: To analyze systemically the prevalence of renal involvement in a cohort of Finnish patients with lysinuric protein intolerance (LPI) and to describe the course and outcome of end-stage renal disease in 4 patients.

Study Design: The clinical information in a cohort of 39 Finnish patients with LPI was analyzed retrospectively.

Results: Proteinuria was observed in 74% of the patients and hematuria was observed in 38% of the patients during follow-up. Elevated blood pressure was diagnosed in 36% of the patients. Mean serum creatinine concentration increased in 38% of the patients, and cystatin C concentration increased in 59% of the patients. Four patients required dialysis, and severe anemia with poor response to erythropoietin and iron supplementation also developed in these patients.

Conclusions: Our findings suggest that renal function of patients with LPI needs to be carefully monitored, and hypertension and hyperlipidemia should be treated effectively. Special attention also should be paid to the prevention of osteoporosis and carnitine deficiency in the patients with end-stage renal disease associated with LPI. The primary disease does not prohibit treatment by dialysis and renal transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2007.01.043DOI Listing
June 2007

Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland.

Eur J Hum Genet 2007 Oct 4;15(10):1079-89. Epub 2007 Apr 4.

Department of Medical Genetics, University of Turku, Turku, Finland.

We have performed an entire-population-based survey of the epidemiology and penetrance of Leber hereditary optic neuropathy (LHON) in Finland - a country that is among the best-studied genetic isolates in the world. During our long-term clinical follow-up period since 1970, we have so far identified 36 LHON families in Finland, comprised of almost 1000 family members. Counting the unaffected family members has been possible thanks to accessible genealogical records, and this has improved the accuracy of our penetrance figures by minimizing the sample bias. Our results, although confirming some well-known features of LHON, indicate that the overall penetrance of LHON is lower than previously estimated, and that affected females have a higher incidence of affected offspring compared to the unaffected females. The prevalence of LHON in Finland is 1:50 000, and one in 9000 Finns is a carrier of one of the three LHON primary mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.ejhg.5201828DOI Listing
October 2007

Long-term oral lysine supplementation in lysinuric protein intolerance.

Metabolism 2007 Feb;56(2):185-9

Department of Pediatrics, University of Turku, 20520 Turku, Finland.

In lysinuric protein intolerance (LPI), defective transport of cationic amino acids at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules leads to decreased intestinal absorption and excessive renal loss of lysine, arginine, and ornithine. Citrulline supplementation partially restores the function of the urea cycle that is impaired by deficiency of arginine and ornithine, but does not correct the chronic lysine deficiency. Previous attempts to supplement lysine orally have been hindered by profuse diarrhea, probably caused by excess lysine remaining unabsorbed in the gut. However, individually adjusted minute doses of L-lysine hydrochloride at mealtimes are tolerated well, but the long-term benefits of this therapy remain unknown. The aim of the study was to investigate the long-term benefits and possible adverse effects of oral lysine supplementation in patients with LPI. Supplementation of meals with low doses of oral lysine improved fasting plasma lysine concentrations in 27 Finnish patients with LPI without causing hyperammonemia or other recognizable side effects during 12 months of follow-up. In conclusion, low-dose oral lysine supplementation is potentially beneficial to patients with LPI and can be started safely at an early age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2006.09.011DOI Listing
February 2007

Two alternative promoters regulate the expression of lysinuric protein intolerance gene SLC7A7.

Mol Genet Metab 2007 Mar 29;90(3):298-306. Epub 2006 Dec 29.

Department of Medical Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.

The human SLC7A7 gene encodes y(+)L amino acid transporter-1 (y(+)LAT-1). Mutations in the SLC7A7 coding region cause a rare recessive disorder, lysinuric protein intolerance (LPI). LPI is enriched in the Finnish population, where all patients carry the same homozygous founder mutation. Although the same LPI genotype is present in all patients, clinical symptoms vary greatly and thus show no genotype-phenotype correlation. In LPI, the transport of cationic amino acids is functionally affected at least at the basolateral membrane of the polarised epithelial cells in the kidney tubules and small intestine, although SLC7A7 is expressed much more widely. Interestingly, some LPI patients' tissues exhibit normal cationic amino acid transport despite the mutations leading to clinical phenotype. When studying the various manifestations of this monogenic disorder and the tissue specificity of the transport defect, it is crucial to know the transcriptional regulatory mechanisms of SLC7A7 gene. In this study, we have identified a novel alternative, TATA-box-containing promoter that plays a role in the tissue-specific regulation of the SLC7A7 gene expression. This newly found downstream promoter in front of exon 2 seems to be active in tissues with strong defects in the function of the transporter in patients with LPI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2006.11.007DOI Listing
March 2007

Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

Eur J Hum Genet 2006 Aug 17;14(8):904-10. Epub 2006 May 17.

1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.ejhg.5201640DOI Listing
August 2006

Regional differences among the Finns: a Y-chromosomal perspective.

Gene 2006 Jul 18;376(2):207-15. Epub 2006 Mar 18.

Finnish Genome Center, University of Helsinki, Finland.

Twenty-two Y-chromosomal markers, consisting of fourteen biallelic markers (YAP/DYS287, M170, M253, P37, M223, 12f2, M9, P43, Tat, 92R7, P36, SRY-1532, M17, P25) and eight STRs (DYS19, DYS385a/b, DYS388, DYS389I/II, DYS390, DYS391, DYS392, DYS393), were analyzed in 536 unrelated Finnish males from eastern and western subpopulations of Finland. The aim of the study was to analyze regional differences in genetic variation within the country, and to analyze the population history of the Finns. Our results gave further support to the existence of a sharp genetic border between eastern and western Finns so far observed exclusively in Y-chromosomal variation. Both biallelic haplogroup and STR haplotype networks showed bifurcated structures, and similar clustering was evident in haplogroup and haplotype frequencies and genetic distances. These results suggest that the western and eastern parts of the country have been subject to partly different population histories, which is also supported by earlier archaeological, historical and genetic data. It seems probable that early migrations from Finno-Ugric sources affected the whole country, whereas subsequent migrations from Scandinavia had an impact mainly on the western parts of the country. The contacts between Finland and neighboring Finno-Ugric, Scandinavian and Baltic regions are evident. However, there is no support for recent migrations from Siberia and Central Europe. Our results emphasize the importance of incorporating Y-chromosomal data to reveal the population substructure which is often left undetected in mitochondrial DNA variation. Early assumptions of the homogeneity of the isolated Finnish population have now proven to be false, which may also have implications for future association studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2006.03.004DOI Listing
July 2006

[From East or West? The genetic roots of Finns].

Duodecim 2006 ;122(1):63-8

Turun yliopiston biolääketieteen laitos, lääketieteellinen genetiikka, Turku.

View Article and Find Full Text PDF

Download full-text PDF

Source
August 2006

Hazards associated with pregnancies and deliveries in lysinuric protein intolerance.

Metabolism 2006 Feb;55(2):224-31

Department of Pediatrics, University of Turku, 20520 Turku, Finland.

Lysinuric protein intolerance (LPI) is an autosomal recessive transport disorder of the dibasic amino acids. The defect leads to deficiency of lysine, arginine, and ornithine and, secondarily, to a functional disorder of the urea cycle. Transient postprandial hyperammonemia and subsequent persistent protein aversion, linked with several other biochemical and clinical characteristics of the disease, suggest an increased risk for maternal and fetal complications during pregnancy and delivery. Our unique material on the outcomes of 18 pregnancies of 9 Finnish mothers with LPI and the follow-up of their 19 children shows that maternal LPI is truly associated with increased risk of anemia, toxemia, and intrauterine growth retardation during pregnancy and bleeding complications during delivery. Successful pregnancies and deliveries can still be achieved with careful follow-up of blood pressure and laboratory values. The children of the mothers with LPI generally develop normally. Special care of maternal protein nutrition and control of ammonemia, anemia, and toxemia during pregnancy are essential. We propose centralization of deliveries to obstetric units with capability to deal with bleeding complications and rare inborn errors of metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2005.08.016DOI Listing
February 2006

Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder.

Am J Hum Genet 2005 Dec 11;77(6):1086-91. Epub 2005 Oct 11.

Mitochondrial Research Group, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/498176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1285165PMC
December 2005

Dominant optic atrophy: correlation between clinical and molecular genetic studies.

Acta Ophthalmol Scand 2005 Jun;83(3):337-46

Department of Medical Genetics, University of Turku, Turku, Finland.

Purpose: To assess the clinical picture and molecular genetics of 14 Finnish families with dominant optic atrophy (DOA).

Methods: The clinical status of family members was based on the assessment of visual acuity, colour vision, visual fields and optic nerve appearance; 31 individuals were affected, two suspect and 21 unaffected. A total of 30 coding exons and exon- intron boundaries of the OPA1 gene were sequenced in order to detect mutations.

Results: Half the patients were diagnosed at the age of < or = 20 years. Ten out of 20 affected individuals followed up for > or = 6 years had a progressive disease and 10 had a stable disease. According to WHO criteria, 36% of the affected patients were visually handicapped. Eight OPA1 pathogenic mutations, all but one novel, and 18 neutral polymorphisms were detected.

Conclusion: The most sensitive indicators of DOA were optic disc pallor and dyschromatopsia. With molecular genetic analysis, asymptomatic mutation carriers and DOA cases with a mild clinical outcome were ascertained. No mutational hotspot or Finnish major mutation in the OPA1 gene could be demonstrated as most families carried a unique mutation. No obvious genotype- phenotype correlation could be detected. Detailed clinical assessment and exclusion of non-DOA families prior to mutation screening are necessary for obtaining a high mutation detection rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1600-0420.2005.00448.xDOI Listing
June 2005

Mitochondrial DNA diversity in indigenous populations of the southern extent of Siberia, and the origins of Native American haplogroups.

Ann Hum Genet 2005 Jan;69(Pt 1):67-89

Laboratory of Human Molecular Genetics, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk 630090, Russia Federation.

In search of the ancestors of Native American mitochondrial DNA (mtDNA) haplogroups, we analyzed the mtDNA of 531 individuals from nine indigenous populations in Siberia. All mtDNAs were subjected to high-resolution RFLP analysis, sequencing of the control-region hypervariable segment I (HVS-I), and surveyed for additional polymorphic markers in the coding region. Furthermore, the mtDNAs selected according to haplogroup/subhaplogroup status were completely sequenced. Phylogenetic analyses of the resulting data, combined with those from previously published Siberian arctic and sub-arctic populations, revealed that remnants of the ancient Siberian gene pool are still evident in Siberian populations, suggesting that the founding haplotypes of the Native American A-D branches originated in different parts of Siberia. Thus, lineage A complete sequences revealed in the Mansi of the Lower Ob and the Ket of the Lower Yenisei belong to A1, suggesting that A1 mtDNAs occasionally found in the remnants of hunting-gathering populations of northwestern and northern Siberia belonged to a common gene pool of the Siberian progenitors of Paleoindians. Moreover, lineage B1, which is the most closely related to the American B2, occurred in the Tubalar and Tuvan inhabiting the territory between the upper reaches of the Ob River in the west, to the Upper Yenisei region in the east. Finally, the sequence variants of haplogroups C and D, which are most similar to Native American C1 and D1, were detected in the Ulchi of the Lower Amur. Overall, our data suggest that the immediate ancestors of the Siberian/Beringian migrants who gave rise to ancient (pre-Clovis) Paleoindians have a common origin with aboriginal people of the area now designated the Altai-Sayan Upland, as well as the Lower Amur/Sea of Okhotsk region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1046/j.1529-8817.2003.00127.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905771PMC
January 2005

Promoter analysis of the human SLC7A7 gene encoding y+L amino acid transporter-1 (y+LAT-1).

Biochem Biophys Res Commun 2003 Feb;301(4):855-61

Department of Medical Genetics, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520, Turku, Finland.

The human SLC7A7 gene on chromosome 14q11.2 encodes the y+L amino acid transporter-1 (y+LAT-1) protein that transports, together with the 4F2hc cell surface antigen, cationic amino acids through the basolateral membrane of epithelial cells in the small intestine and kidney. The SLC7A7 gene comprises 11 exons, but the first two are not translated. Mutations in the coding region of the SLC7A7 gene cause a rare autosomal disorder, lysinuric protein intolerance (LPI). We have now investigated the expression levels and putative 5' promoter elements of the SLC7A7. The 5' region of the first untranslated exon contains no TATA-box, Inr elements nor other classical promoter elements, but has instead other putative transcription factor binding sequences. The E-box and AP-2 elements were able to bind proteins in HEK293 cells and adult kidney tissue extracts, but not in fibroblasts. Using transient transfection and luciferase reporter gene studies, we showed that the first two introns located in the untranslated region contained transcriptional enhancer elements. Northern blot analysis showed low and equal SLC7A7 mRNA levels in the control and LPI patient fibroblastoid and lymphoblast cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0006-291x(03)00054-8DOI Listing
February 2003

Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic LHON families.

J Neurol Sci 2002 Dec;205(1):41-5

Department of Medical Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.

Leber hereditary optic neuropathy (LHON) is an ocular disease associated with mutations in the mitochondrial DNA (mtDNA). The level of heteroplasmy in the mtDNA mutations ND4/11778 and ND1/3460 was followed over a period of 4-12 years in blood samples taken from nine members of four heteroplasmic LHON families. In addition, hair follicle and urinary tract epithelium samples of one individual were studied. The quantification of heteroplasmy was performed using the solid-phase minisequencing method. Only minor and random shifts in the heteroplasmy levels were observed over time, but there were no systematic changes towards an increasing or decreasing proportion of either LHON mutant in the individuals. This indicates that there is no selection for either mtDNA genotype but the segregation of the wild-type mtDNAs and those carrying LHON mutations is a stochastic process governed by random genetic drift. In this respect, LHON mutations seem to behave like neutral polymorphisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0022-510x(02)00276-9DOI Listing
December 2002

A rare mitochondrial DNA haplotype observed in Koreans.

Hum Biol 2002 Apr;74(2):253-62

Department of Biology, University of Turku, Finland.

The haplogroup affiliations of Korean mitochondrial DNAs (mtDNAs) were determined by restriction analysis. Out of the 101 mtDNAs analyzed, 91 (90%) belonged to Asian-specific haplogroups M, C, D, G, A, B, and F. Haplogroup E was not detected among the Korean mtDNAs. Three mtDNAs represented an unusual mtDNA haplotype characterized by simultaneous presence of E and G haplogroup-specific polymorphisms. To characterize this haplotype in more detail, we sequenced the hypervariable segment I (HVSI) from these mtDNAs as well as from those from selected individuals representing each haplogroup. Sequence data were further used to compare Korean mtDNAs with mtDNAs from other Asian populations. The observed rare haplotype was also found among Japanese, which suggests that it is one of the ancestral lineages originally peopling Japan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1353/hub.2002.0024DOI Listing
April 2002

Genetic counseling in Leber hereditary optic neuropathy (LHON).

Acta Ophthalmol Scand 2002 Feb;80(1):38-43

Department of Medical Genetics, University of Turku, Finland.

Purpose: To demonstrate the importance of mitochondrial DNA (mtDNA) analysis in the diagnosis of Leber hereditary optic neuropathy (LHON) and illustrate the difficulties in genetic counseling of the disease.

Participants And Methods: Ophthalmological and molecular genetic study of one affected and three unaffected members from a family with heteroplasmic ND1/3460 mtDNA mutation associated with LHON.

Results: The proband had variable amounts of mutant mtDNA in all his tissues studied, ranging from 58% in blood to 92% in subcutis. The mother had an extremely low amount of mutant mtDNA in her tissues, except for hair roots, which contained only normal mtDNA. No mutant mtDNA could be detected in the proband's unaffected sister and maternal aunt.

Conclusions: Despite her minimal mutation load, the mother of the proband has still transmitted a considerable amount of mutant mtDNA to her son, who is severely affected. Although proband's unaffected sister and maternal aunt had no mutant mtDNA, a theoretical risk that they may transmit the disease to their offspring cannot be excluded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1034/j.1600-0420.2002.800108.xDOI Listing
February 2002

Expression of normal and mutant GFP-tagged y(+)L amino acid transporter-1 in mammalian cells.

Biochem Biophys Res Commun 2002 Mar;291(5):1173-9

Department of Medical Genetics, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.

Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive disorder characterized by defective transport of cationic amino acids lysine, arginine and ornithine. The defect is localized in the basolateral membrane of polar epithelial cells of the renal tubules and intestine. The SLC7A7 (solute carrier family 7, member 7) gene that encodes y(+)LAT-1 (y(+)L amino acid transporter-1) is mutated in LPI, and leads to the malfunction of the heterodimer composed of y(+)LAT-1 and 4F2hc (4F2 heavy chain) responsible for the system y(+)L amino acid transport activity at the membrane. In this study, the intracellular trafficking and membrane expression of wild type and four mutant y(+)LAT-1 proteins (LPI(Fin), G54V, 1548delC, W242X) was studied in two human cell lines by expressing green fluorescent protein (GFP) tagged proteins. Different SLC7A7 mutations influenced the trafficking of y(+)LAT-1 in the cells differently, as the wild type and missense mutant fusion proteins localized to the plasma membrane, while the frameshift and nonsense mutants sequestered to the cytoplasmic membranes, never reaching the target areas of the cell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1006/bbrc.2002.6564DOI Listing
March 2002
-->