| 1. |
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| 2. |
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| 3. |
- Borg, Kristian, et al.
(författare)
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Intragenic deletion of TRIM32 in compound heterozygotes with sarcotubular myopathy/LGMD2H
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:9, s. E831-E844
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Tidskriftsartikel (refereegranskat)abstract
- In 2005 the commonality of sarcotubular myopathy (STM) and limb girdle muscular dystrophy type 2H (LGMD2H) was demonstrated, as both are caused by the p D487N missense mutation in TRIM32 originally found in the Manitoba Hutterite population. Recently, three novel homozygous TRIM32 mutations have been described in LGMD patients. Here we describe a three generation Swedish family clinically presenting with limb girdle muscular weakness and histological features of a microvacuolar myopathy. The two index patients were compound heterozygotes for a frameshift mutation in TRIM32 (c.1560delC ) and a 30 kb intragenic deletion, encompassing parts of intron 1 and the entire exon 2 of TRIM32. In these patients, no full-length or truncated TRIM32 could be detected. Interestingly, heterozygous family members carrying only one mutation showed mild clinical symptoms and vacuolar changes in muscle. In our family, the phenotype encompasses additionally a mild demyelinating polyneuropathic syndrome. Thus STM and LGMD2H are the result of loss of function mutations that can be either deletions or missense mutations. (c) 2009 Wiley-Liss, Inc.
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| 4. |
- Buckley, Patrick G., et al.
(författare)
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Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
- 2005
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:6, s. 540-9
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Tidskriftsartikel (refereegranskat)abstract
- Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.
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| 5. |
- Charbonnier, FC, et al.
(författare)
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The 5 ' Region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences
- 2005
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:3, s. 255-261
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Tidskriftsartikel (refereegranskat)abstract
- MSH2 rearrangements are involved in approximately 10% of hereditary non,polyposis colorectal cancer (HNPCC) families, and in most of the rearrangements, exon I is deleted. We scanned by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) 200 kb of genomic sequences upstream of the MSH2 transcription initiation site in 21 HNPCC families with exon I deletions. This QMPSF scan revealed 12 distinct 5' breakpoints located up to 200 kb upstream of the MSH2 transcription initiation site. Sequencing analysis of the rearranged allele in 17 families revealed that most of the deletions (15/17) resulted from homologous Alu-mediated recombination. QMPSF and sequencing analysis in these 21 families led us to detect the presence of 20 distinct 5' breakpoints. In 14 out of 15 Alu-mediated recombinations, we found, either within the identical region in which the recombination had probably occurred or in its vicinity, the 26,bp Alu core sequence containing the recombinogenic Chi-like motif. Compared to the equivalent regions of other human genes, the MSH2 upstream region was found to contain a high density of Alu repeats (30% within 228 kb and 43% within 50 kb), most of which belong to the old Alu S subfamilies. In conclusion, this study demonstrates the heterogeneity of the breakpoints within the MSH2 upstream region and reveals the remarkable density of recombinogenic Alu sequences in this region.
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| 6. |
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| 7. |
- Clendenning, M, et al.
(författare)
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Long-range PCR facilitates the identification of PMS2-specific mutations
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:5, s. 490-495
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Tidskriftsartikel (refereegranskat)abstract
- Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and I I endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G > T, c.736-741del6ins11, c.862_863del, c.1688G > T, and c.2007-IG > A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable.
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| 8. |
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| 9. |
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| 10. |
- de Ståhl, Teresita Díaz, et al.
(författare)
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Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 29:3, s. 398-408
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Tidskriftsartikel (refereegranskat)abstract
- To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.
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| 11. |
- Dreyer, Bo, et al.
(författare)
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Spectrum of USH2A mutations in Scandinavian patients with Usher Syndrome type II
- 2008
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Ingår i: Human Mutation. - : Wiley-Liss. - 1059-7794 .- 1098-1004. ; 29:3, s. 451-451
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Tidskriftsartikel (refereegranskat)abstract
- Usher syndrome type II (USH2) is an autosomal recessive disorder, characterised by moderate to severe high-frequency hearing impairment, normal balance function and progressive visual impairment due to retinitis pigmentosa. Usher syndrome type IIa, the most common subtype, is defined by mutations in the USH2A gene encoding a short and a recently discovered long usherin isoform comprising 21 and 73 exons, respectively. More than 120 different disease-causing mutations have been reported, however, most of the previous reports concern mutations restricted to exons 1-21 of the USH2A gene. To explore the spectrum of USH2A disease-causing mutations among Scandinavian USH2 cases, patients from 118 unrelated families of which 27 previously had been found to carry mutations in exons 1-21 were subjected to extensive DNA sequence analysis of the full size USH2A gene. Altogether, 122 USH2A DNA sequence alterations were identified of which 57 were predicted to be disease-causing, 7 were considered to be of uncertain pathogenicity and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations 31 were located in exons 22-73, specific to the long isoform. USH2A mutations were identified in 89/118 (75.4%) families. In 79/89 (88.8%) of these families two pathogenic mutations were identified whereas in 10/89 (11.2%) families the second mutation remained unidentified. In 5/118 (4.2%) families the USH phenotype could be explained by mutations in the USH3A gene. The results presented here provide a comprehensive picture of the genetic aetiology of Usher syndrome type IIA in Scandinavia as it is known to date.
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| 12. |
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| 13. |
- Goossens, Dirk, et al.
(författare)
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Simultaneous mutation and copy number variation (CNV) detection by multiplex PCR-based GS-FLX sequencing.
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:3, s. 472-6
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated multiplex PCR amplification as a front-end for high-throughput sequencing, to widen the applicability of massive parallel sequencers for the detailed analysis of complex genomes. Using multiplex PCR reactions, we sequenced the complete coding regions of seven genes implicated in peripheral neuropathies in 40 individuals on a GS-FLX genome sequencer (Roche). The resulting dataset showed highly specific and uniform amplification. Comparison of the GS-FLX sequencing data with the dataset generated by Sanger sequencing confirmed the detection of all variants present and proved the sensitivity of the method for mutation detection. In addition, we showed that we could exploit the multiplexed PCR amplicons to determine individual copy number variation (CNV), increasing the spectrum of detected variations to both genetic and genomic variants. We conclude that our straightforward procedure substantially expands the applicability of the massive parallel sequencers for sequencing projects of a moderate number of amplicons (50-500) with typical applications in resequencing exons in positional or functional candidate regions and molecular genetic diagnostics.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Kosoy, Roman, et al.
(författare)
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Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:1, s. 69-78
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Tidskriftsartikel (refereegranskat)abstract
- To provide a resource for assessing continental ancestry in a wide variety of genetic studies, we identified, validated, and characterized a set of 128 ancestry informative markers (AIMs). The markers were chosen for informativeness, genome-wide distribution, and genotype reproducibility on two platforms (TaqMan assays and Illumina arrays). We analyzed genotyping data from 825 subjects with diverse ancestry, including European, East Asian, Amerindian, African, South Asian, Mexican, and Puerto Rican. A comprehensive set of 128 AIMs and subsets as small as 24 AIMs are shown to be useful tools for ascertaining the origin of subjects from particular continents, and to correct for population stratification in admixed population sample sets. Our findings provide general guidelines for the application of specific AIM subsets as a resource for wide application. We conclude that investigators can use TaqMan assays for the selected AIMs as a simple and cost efficient tool to control for differences in continental ancestry when conducting association studies in ethnically diverse populations.
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| 18. |
- Kroos, Marian, et al.
(författare)
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Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.
- 2008
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Ingår i: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 29:6
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Tidskriftsartikel (refereegranskat)abstract
- Pompe disease was named after the Dutch pathologist Dr JC Pompe who reported about a deceased infant with idiopathic hypertrophy of the heart. The clinical findings were failure to thrive, generalized muscle weakness and cardio-respiratory failure. The key pathologic finding was massive storage of glycogen in heart, skeletal muscle and many other tissues. The disease was classified as glycogen storage disease type II and decades later shown to be a lysosomal disorder caused by acid alpha-glucosidase deficiency. The clinical spectrum of Pompe disease appeared much broader than originally recognized. Adults with the same enzyme deficiency, alternatively named acid maltase deficiency, were reported to have slowly progressive skeletal muscle weakness and respiratory problems, but no cardiac involvement. The clinical heterogeneity is largely explained by the kind and severity of mutations in the acid alpha-glucosidase gene (GAA), but secondary factors, as yet unknown, have a substantial impact. The Pompe disease mutation database aims to list all GAA sequence variations and describe their effect. This update with 107 sequence variations (95 being novel) brings the number of published variations to 289, the number of non-pathogenic mutations to 67 and the number of proven pathogenic mutations to 197. Further, this article introduces a tool to rate the various mutations by severity, which will improve understanding of the genotype-phenotype correlation and facilitate the diagnosis and prognosis in Pompe disease.
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| 19. |
- Lahermo, P, et al.
(författare)
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A quality assessment survey of SNP genotyping laboratories
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:7, s. 711-714
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.
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| 20. |
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| 21. |
- Lindstrom, E, et al.
(författare)
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PTCH mutations: distribution and analyses
- 2006
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Ingår i: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 27:3, s. 215-219
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Tidskriftsartikel (refereegranskat)
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| 22. |
- Oshima, A., et al.
(författare)
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Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I
- 2008
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Ingår i: Human Mutation. - New York, N.Y. : Wiley-Liss. - 1059-7794 .- 1098-1004. ; 29:6, s. E37-E46
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the human gene encoding cadherin 23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations.
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| 23. |
- Pettersson, Erik, et al.
(författare)
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Allelotyping by massively parallel pyrosequencing of SNP-carrying trinucleotide threads
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 29:2, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- Here we present an approach for allelotyping combining the multiplexing features of the trinucleotide threading (TnT) method with pooling of genomic DNA and massively parallel pyrosequencing, enabling reliable allele frequency estimation in large cohorts. The approach offers several benefits as compared to array-based methods and allows undertaking highly complex studies without compromising accuracy, while keeping the workload to a minimum. This proof-of-concept study involves formation of trinucleotide threads, targeting a total of 147 single-nucleotide polymorphisms (SNPs) related to obesity and cancer, for multiplex amplification and allele extraction from a pool of 462 genomes, followed by massively parallel pyrosequencing. Approximately 177k reads were approved, identified, and assigned to SNP-carrying threads rendering representative allele frequencies in the cohort.
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| 24. |
- Piotrowski, Arkadiusz, et al.
(författare)
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Somatic mosaicism for copy number variation in differentiated human tissues
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 29:9, s. 1118-24
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Tidskriftsartikel (refereegranskat)abstract
- Two major types of genetic variation are known: single nucleotide polymorphisms (SNPs), and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. We tested 34 tissue samples from three subjects and, having analyzed for each tissue < or =10(-6) of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82 to 176 kb, often encompassing known genes, potentially affecting gene function. Our results indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. The majority of described CNVs were previously shown to be polymorphic between unrelated subjects, suggesting that some CNVs previously reported as germline might represent somatic events, since in most studies of this kind, only one tissue is typically examined and analysis of parents for the studied subjects is not routinely performed. A considerable number of human phenotypes are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues to better address mosaicism in the studies of somatic disorders.
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| 25. |
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| 26. |
- Reynolds, Chandra A, et al.
(författare)
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A survey of ABCA1 sequence variation confirms association with dementia.
- 2009
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Ingår i: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 30:9, s. 1348-54
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Tidskriftsartikel (refereegranskat)abstract
- We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
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| 27. |
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| 28. |
- Rohlin, Anna, et al.
(författare)
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Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques.
- 2009
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Ingår i: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 30:6, s. 1012-20
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Tidskriftsartikel (refereegranskat)abstract
- We have made an evaluation of mutation detection techniques for their abilities to detect mosaic mutations. In this study, Sanger sequencing, single-strand conformation polymorphism (SSCP)/heteroduplex analysis (HD), protein truncation test (PTT), and denaturating high-performance liquid chromatography (DHPLC) were compared with parallel sequencing. In total DNA samples from nine patients were included in this study. Mosaic mutations were artificially constructed from seven of these samples, which were from heterozygote mutation carriers with the mutant allele present at 50%. The mutations analyzed were as follows: c.646C>T, c.2626C>T, c.2828C>A, c.1817_1818insA, c.2788dupA, c.416_419delAAGA, and c.607delC in the APC gene. The lowest degree of mutant alleles detected with SSCP/HD and DHPLC varied between 5% and 25%, and between 15% and 50% for Sanger sequencing. Three of the mutations were analyzed with PTT with considerable variations in detection levels (from 10 to 100%). Using parallel sequencing a detection frequency down to 1% was reached, but to achieve this high sensitivity sufficient coverage was required. Two patients with natural mosaic mutations were also included in this study. These two mutations had previously been identified with Sanger sequencing (NF2 c.1026_1027delGA) and SSCP/HD (APC c.2700_2701delTC). In conclusion, all the evaluated methods are applicable for mosaic mutation screening even though combinations of the conventional methods should be used to reach an adequate sensitivity. Sanger sequencing alone is not sensitive enough to detect low mosaic levels. Parallel sequencing seems to be the ultimate choice but the possibilities to use this technique is today limited by its complexity, economics, and availability of instruments.
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| 29. |
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Van Laer, Lut, et al.
(författare)
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The contribution of genes involved in potassium-recyclingin the inner ear to noise-induced hearing loss
- 2006
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 27:8, s. 786-795
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Tidskriftsartikel (refereegranskat)abstract
- Noise-induced hearing loss (NIHL) is one of the most important occupational diseases and, after presbyacusis, the most frequent cause of hearing loss. NIHL is a complex disease caused by an interaction between environmental and genetic factors. The various environmental factors involved in NIHL have been relatively extensively studied. On the other hand, little research has been performed on the genetic factors responsible for NIHL. To test whether the variation in genes involved in coupling of cells and potassium recycling in the inner ear might partly explain the variability in susceptibility to noise, we performed a case-control association study using 35 SNPs selected in 10 candidate genes on a total of 218 samples selected from a population of 1,261 Swedish male noise,exposed workers. We have obtained significant differences between susceptible and resistant individuals for the allele, genotype, and haplotype frequencies for three SNPs of the KCNEI gene, and for the allele frequencies for one SNP of KCNQ1 and one SNP of KCNQ4. Patch-clamp experiments in high K+-concentrations using a Chinese hamster ovary (CHO) cell model were performed to investigate the possibility that the KCNE1-p.85N variant (NT_011512.10:g.21483550G > A; NP_00210.2:p.Asp85Asn) was causative for high noise susceptibility. The normalized current density generated by KCNQ1/KCNE1-p.85N channels, thus containing the susceptibility variant, differed significantly from that from wild-type channels. Furthermore, the midpoint potential of KCNQ1/KCNE1-p.85N channels (i.e., the voltage at which 50% of the channels are open) differed from that of wild-type channels. Further genetic and physiological studies will be necessary to confirm these findings.
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| 34. |
- Visser, W Edward, et al.
(författare)
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Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations
- 2009
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 30:1, s. 29-38
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Tidskriftsartikel (refereegranskat)abstract
- Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Staaf, Johan, et al.
(författare)
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Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH).
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794. ; 29:4, s. 555-564
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Tidskriftsartikel (refereegranskat)abstract
- Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic hybridization (CGH) platform of 60mer oligonucleotides. The 4 x 44 K array format provides high-resolution coverage (200-300 bp) of 400-700 kb genomic regions surrounding six cancer susceptibility genes. We evaluate its performance to accurately detect and precisely map earlier described or novel large germline deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged from several 100 kb, including large flanking regions, to <500-bp deletions, including parts of single exons that would be missed by standard multiplex ligation-dependent probe amplification (MLPA) methods. Zoom-in CGH arrays accurately defined the borders of rearrangements, allowing convenient design of primers for sequence determination of the breakpoints. The array platform can be streamlined for a particular application, e.g., focusing on breast cancer susceptibility genes, with increased capacity using multiformat design, and represents a valuable new tool and complement for genetic screening in clinical diagnostics.
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| 39. |
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