| 1. |
- Fellman, Vineta, et al.
(författare)
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Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause
- 2008
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 53:6, s. 554-558
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Tidskriftsartikel (refereegranskat)abstract
- The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III (CIII). A homozygous point mutation (232A -> G) has been found as the genetic etiology for fetal growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome (MIM 603358). Variable phenotypes have been found with other mutations. Our aim was to assess whether 232A -> G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder. A further aim was to confirm the GRACILE genotype-phenotype constancy (n = 8). Three new cases with homozygous 232A -> G mutation were identified; all had the primary GRACILE characteristics. No other mutations were found in the gene in other cases. All infants with GRACILE syndrome had the typical mutation. In conclusion, the rather homogenous population of Finns seems to have a specific BCS1L mutation that, as homozygous state, causes GRACILE syndrome, whereas other mutations are rare or not occurring. Thus, the novel clinical implication of this study is to screen for BCS1L mutations only if CIII is dysfunctioning or lacking Rieske protein, and to assess 232A -> G mutation in cases with GRACILE syndrome.
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| 4. |
- Melin, Malin, et al.
(författare)
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A founder mutation for ichthyosis prematurity syndrome restricted to 76 kb by haplotype association
- 2006
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 51:10, s. 864-871
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive congenital ichthyosis (ARCI) is a group of keratinisation disorders that includes the ichthyosis prematurity syndrome (IPS). IPS is rare and almost exclusively present in a restricted region in the middle of Norway and Sweden, which indicates a founder effect for the disorder. We recently reported linkage of IPS to chromosome 9q34, and we present here the subsequent fine-mapping of this region with known and novel microsatellite markers as well as single nucleotide polymorphisms (SNPs). Allelic association, evaluated with Fisher's exact test and P (excess), was used to refine the IPS haplotype to approximately 1.6 Mb. On the basis of the average length of the haplotype in IPS patients, we calculated the age of a founder mutation to approximately 1,900 years. The IPS haplotype contains a core region of 76 kb consisting of four marker alleles shared by 97.7% of the chromosomes associated with IPS. This region spans four known genes, all of which are expressed in mature epidermal cells. We present the results from the analysis of these four genes and their corresponding transcripts in normal and patient-derived samples.
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| 5. |
- Rajic, Zoran A, et al.
(författare)
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Size of the protein-coding genome and rate of molecular evolution.
- 2005
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 50:5, s. 217-29
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Tidskriftsartikel (refereegranskat)abstract
- In diploid populations of size N, there will be 2 Nmu mutations per nucleotide (nt) site (or per locus) per generation (mu stands for mutation rate). If either the population or the coding genome double in size, one expects 4 Nmu mutations. What is important is not the population size per se but the number of genes (coding sites), the two being often interconverted. Here we compared the total physical length of protein-coding genomes (n) with the corresponding absolute rates of synonymous substitution (K(S)), an empirical neutral reference. In the classical occupancy problem and in the coupons collector (CC) problem, n was expressed as the mean rate of change (K(CC)). Despite inherently very low power of the approaches involving averaging of rates, the mode of molecular evolution of the total size phenotype of the coding genome could be evidenced through differences between the genomic estimates of K(CC) [K(CC)=1/(ln n + 0.57721) n] and rate of molecular evolution, K(S). We found that (1) the estimates of n and K(S) are reciprocally correlated across taxa (r=0.812; p<< 0.001); (2) the gamete-cell division hypothesis (Chang et al. Proc Natl Acad Sci USA 91:827-831, 1994) can be confirmed independently in terms of K(CC)/K(S) ratios; (3) the time scale of molecular evolution changes with change in mutation rate, as previously shown by Takahata (Proc Natl Acad Sci USA 87:2419-2423, 1990), Takahata et al. (Genetics 130:925-938, 1992), and Vekemans and Slatkin (Genetics 137:1157-1165, 1994); (4) the generation time and population size (Lynch and Conery, Science 302:1401-1404, 2003) effects left their "signatures" at the level of the size phenotype of the protein-coding genome.
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| 6. |
- Rasool, Mahmood, et al.
(författare)
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A novel missense mutation in the EDA gene associated with X-linked recessive isolated hypodontia
- 2008
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 53:10, s. 894-8
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Tidskriftsartikel (refereegranskat)abstract
- Isolated hypodontia, or congenital absence of one to six permanent teeth (OMIM 300606), is a common condition that affects about 20% of individuals worldwide. We identified two extended Pakistani pedigrees segregating X-linked hypodontia with variable expressivity. Affected males show no other associated anomalies, and obligate carrier females have normal dentition. We analyzed the families with polymorphic markers in the ectodysplasin A (EDA) gene region and obtained significant linkage to the phenotype in each pedigree (Z(max) 3.29 and 2.65, respectively, at theta = 0.00). Sequence analysis of the coding regions of EDA revealed a novel missense mutation c.1091T>C resulting in a methionine to threonine substitution (p.M364T) in the tumor necrosis factor (TNF) homology domain. Met364 is a highly conserved residue located on the outer surface of the EDA protein. From our findings, we suggest that the mutation disturbs but does not destroy the EDA structure, resulting in the partial and unusually mild ED phenotype restricted to hypodontia.
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