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| 2. |
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| 3. |
- Bondeson, Marie-Louise, et al.
(author)
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Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome
- 1995
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In: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 4:4, s. 615-621
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Journal article (peer-reviewed)abstract
- We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.
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| 4. |
- Bondeson, Marie-Louise, et al.
(author)
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Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome
- 1995
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In: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 3:4, s. 219-227
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Journal article (peer-reviewed)abstract
- A deficiency of the enzyme iduronate-2-sulfatase (IDS) is the cause of Hunter syndrome (mucopolysaccharidosis type II). Here, we report a study of the human IDS locus at Xq28. An unexpected finding was an IDS-related region (IDS2) which is located on the telomeric side of the IDS gene within 80 kb. We have identified sequences in this locus that are homologous to exons 2 and 3 as well as sequences homologous to introns 2, 3 and 7 of the IDS gene. The exon 3 sequences in the IDS gene and in the IDS2 locus showed 100% identity. The overall identities of the other identified regions were 96%. A locus for DXS466 was also found to be located close to IDS2. The existence of the IDS2 locus complicates the diagnosis of mutations in genomic DNA from patients with Hunter syndrome. However, information about the IDS2 locus makes it possible to analyze the IDS gene and the IDS2 locus separately after PCR amplification.
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| 5. |
- Gudmundsson, Sanna, et al.
(author)
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Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
- 2017
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In: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:6, s. 1070-1077
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Journal article (peer-reviewed)abstract
- Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
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| 7. |
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| 8. |
- Karsten, Stanislav L., et al.
(author)
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Two distinct deletions in the IDS gene and the gene W : a novel type of mutation associated with the Hunter syndrome
- 1997
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In: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 43:2, s. 123-129
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Journal article (peer-reviewed)abstract
- A novel mutation has been identified in a patient with the Hunter syndrome (mucopolysaccharidosis type II), in whom the disorder is associated with two distinct deletions separated by 30 kb. The deletions were characterized by Southern blot and PCR analyses, and the nucleotide sequences at both junctions were determined. The first deletion, corresponding to a loss of 3152 bp of DNA, included exons 5 and 6 of the iduronate-2-sulfatase (IDS) gene. The second deletion was 3603 bp long and included exons 3 and 4 of geneW, which is located in the DXS466 locus telomeric of theIDSgene. Both deletions are the result of nonhomologous (illegitimate) recombination events between short direct repeats at the deletion breakpoints. An interesting finding was the presence of the heptamer sequence 5′-TACTCTA-3′ present at both deletion junctions, suggesting that this motif might be a hot spot for recombination. We propose that the double deletion is the result of homology-associated nonhomologous recombinations caused by the presence of large duplicated regions in Xq27.3–q28.
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| 9. |
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| 10. |
- Lagerstedt, Kristina, et al.
(author)
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Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome
- 1997
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 6:4, s. 627-633
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Journal article (peer-reviewed)abstract
- We have previously shown that patients with the Hunter syndrome frequently have suffered from a recombination event between the IDS gene and its putative pseudogene, IDS-2, resulting in an inversion of the intervening DNA. The inversion, which might be the consequence of an intrachromosomal mispairing, is caused by homologous recombination between sequences located in intron 7 of the IDS gene and sequences located distal of exon 3 in IDS-2. In order to gain insight into the mechanisms causing the inversion, we have isolated both inversion junctions in six unrelated patients. DNA sequence analysis of the junctions showed that all recombinations have taken place within a 1 kb region where the sequence identity is >98%. An interesting finding was the identification of regions with alternating IDS gene and IDS-2 sequences present at one inversion junction, suggesting that the recombination event has been initiated by a double-strand break in intron 7 of the IDS gene. The results from this study suggest that homologous recombination in man could be explained by mechanisms similar to those described for Saccharomyces cerevisiae. The results also have practical implications for diagnosis of patients with the Hunter syndrome.
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| 11. |
- Malmgren, Helena, et al.
(author)
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Identification of an alternative transcript fromthe human iduronate-2-sulfatase (IDS) gene
- 1995
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In: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 29:1, s. 291-293
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Journal article (peer-reviewed)abstract
- Iduronate-2-sulfatase (IDS) is involved in the degradation of heparan sulfate and dermatan sulfate in the lysosomes, and a deficiency in this enzyme results in Hunter syndrome. A 2.3-kb cDNA clone that contains the entire coding sequence of IDS has previously been reported. Here we describe the identification of a 1.4-kb transcript that may encode an IDS-like enzyme. The predicted protein is identical to the previously described enzyme, except for the absence of the 207-amino-acid COOH-terminal domain, which is replaced by 7 amino-acids. Our data suggest that there might exist an additional form of the IDS enzyme in humans. The results from this study may have implications for the pathogenesis of the Hunter syndrome.
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| 12. |
- Winberg, Johanna, et al.
(author)
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Chimerism Resulting From Parthenogenetic Activation and Dispermic Fertilization
- 2010
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In: American Journal of Medical Genetics, Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 152A:9, s. 2277-2286
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Journal article (peer-reviewed)abstract
- Whole-body human chimerism is the result of two zygotes giving rise to one individual, and is a rarely detected condition. We have studied the molecular background and discuss the likely mechanism for the chimerism in a patient with a 46,XX/47,XY,+14 karyotype and ambiguous genitalia, cryptorchidism, pigment anomalies, and normal psychomotor development. We have used karyotyping, interphase-FISH and array-CGH analysis as well as molecular analysis of polymorphic markers from 48 loci in order to define the origin and percentage of 47,XY,+14 cells in different tissues. Based on the findings of two paternal alleles and the detection of homozygous maternal alleles without evidence of crossing-over, and the fact that four alleles were never detected, our results indicate that the chimerism in our patient is the result of dispermic fertilization of a parthenogenetically activated oocyte. Our report underlines that cytogenetic findings suggesting mosaicism might actually indicate chimerism as an underlying mechanism in patients. It also highlights the difficulties in predicting the clinical outcome in patients with genetic aberrations in mosaic or chimeric form.
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| 13. |
- Allanson, Judith E., et al.
(author)
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Cardio-Facio-Cutaneous Syndrome : Does Genotype Predict Phenotype?
- 2011
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In: American Journal of Medical Genetics, Part C: Seminars in Medical Genetics. - : Wiley. - 1552-4868. ; 157C:2, s. 129-135
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Journal article (peer-reviewed)abstract
- Cardio-facio-cutaneous (CFC) syndrome is a sporadic multiple congenital anomalies/mental retardation condition principally caused by mutations in BRAF, MEK1, and MEK2. Mutations in KRAS and SHOC2 lead to a phenotype with overlapping features. In approximately 10-30% of individuals with a clinical diagnosis of CFC, a mutation in one of these causative genes is not found. Cardinal features of CFC include congenital heart defects, a characteristic facial appearance, and ectodermal abnormalities. Additional features include failure to thrive with severe feeding problems, moderate to severe intellectual disability and short stature with relative macrocephaly. First described in 1986, more than 100 affected individuals are reported. Following the discovery of the causative genes, more information has emerged on the breadth of clinical features. Little, however, has been published on genotype-phenotype correlations. This clinical study of 186 children and young adults with mutation-proven CFC syndrome is the largest reported to date. BRAF mutations are documented in 140 individuals (similar to 75%), while 46 (similar to 25%) have a mutation in MEK 1 or MEK 2. The age range is 6 months to 32 years, the oldest individual being a female from the original report [Reynolds et al. (1986); Am J Med Genet 25:413-427]. While some clinical data on 136 are in the literature, 50 are not previously published. We provide new details of the breadth of phenotype and discuss the frequency of particular features in each genotypic group. Pulmonary stenosis is the only anomaly that demonstrates a statistically significant genotype-phenotype correlation, being more common in individuals with a BRAF mutation.
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| 14. |
- Baranowska Körberg, Izabella, et al.
(author)
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A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report
- 2020
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In: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 21:1
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Journal article (peer-reviewed)abstract
- Background ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.
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| 15. |
- Bondeson, Marie-Louise, 1960-, et al.
(author)
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A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
- 2017
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In: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 510-516
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Journal article (peer-reviewed)abstract
- Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.
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| 16. |
- Bondeson, Marie-Louise, et al.
(author)
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Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin
- 2006
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In: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 86:6, s. 503-508
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Journal article (peer-reviewed)abstract
- Neuroectodermal syndromes involving the skin and inner ear may be associated with mutations in connexin proteins, which form gap junctions important for intercellular communication. Vohwinkel syndrome (keratodermia mutilans with hearing loss) and keratitis-ichthyosis-deafness (KID) syndrome are rare ectodermal dysplasias associated with dominant mutations in the GJB2 gene encoding connexin 26. We report here two patients, one with KID and one with Vohwinkel syndrome. Both displayed unusual clinical features and responded well to long-term treatment with oral retinoid. Mutation analysis revealed a novel GJB2 mutation p.Gly59Ser in the patient with Vohwinkel syndrome, whereas a recurrent mutation (p.Asp50Asn) was found in the patient with KID syndrome. The clinical features, particularly a proneness to skin cancer in the patient with Vohwinkel syndrome, are discussed in relation to the identified genotypes.
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| 20. |
- Carlsson, Per Inge, et al.
(author)
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The influence of genetic factors, smoking and cardiovascular disease on human noise susceptibility
- 2007
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In: Audiological Medicine. - : Informa UK Limited. - 1651-386X .- 1651-3835. ; 5:2, s. 82-91
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Journal article (peer-reviewed)abstract
- Noise has a metabolic and mechanical effect on the inner ear and may therefore interfere with gap junction channels, thus disrupting the interaction between cells in the cochlea. Studies have shown that carriers of connexin mutations in genes involved in HI may have some disturbance in auditory function and may be more susceptible to damage caused by, e.g. noises. Furthermore, hair cell damage in the cochlea as a result of noise exposure can also be mediated by reactive oxygen species. Smoking in combination with elevated diastolic blood pressure and presence of the Raynaud's disease (white finger disease) seems to aggravate noise induced hearing loss (NIHL). In the present study we investigated whether interaction between connexin mutations (C26 and C30) alone, or in combination with genetic variability in the cochlear antioxidant system (GSTM1 deletion, GSTT1 deletion), could explain differences in human noise susceptibility. Furthermore, smoking habits and cardiovascular factors (hypertension, heart disease and white finger diseases) were correlated with noise susceptibility and interactions between genetic factors. Smoking and cardiovascular factors were analysed and correlated with the differences in noise susceptibility found in a Swedish noise-exposed population. The results revealed that smoking alone seems to increase noise susceptibility, and that null-genotypes for the GSTM1 gene in the protective antioxidant system, who smoke/have ever smoked had an additional risk for NIHL compared to those who do not smoke/have never smoked.
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| 21. |
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| 22. |
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| 23. |
- Carlsson, Per-Inge, et al.
(author)
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The influence of genetic variation in oxidative stress genes on human noise susceptibility
- 2005
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In: Hearing Research. - 0378-5955 .- 1878-5891. ; 202:1-2, s. 87-96
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Journal article (peer-reviewed)abstract
- Noise induced hearing loss (NIHL) is a complex disease caused by an interaction between genetic and environmental factors. Damage in the cochlea as a result of noise exposure appears to be mediated by reactive oxygen species (ROS). To investigate whether genetic variation in the human protective antioxidant system is associated with high or low susceptibility to NIHL, genetic polymorphisms derived from genes involved in the oxidative stress response were analysed in the 10% most susceptible and 10% most resistant extremes of 1200 Swedish noise-exposed workers. The genetic polymorphisms included 2 deletion polymorphisms for the GSTM1 and GSTT1 gene, and 14 SNPs derived from the CAT, SOD, GPX, GSR and GSTP1 genes. No significant differences were found between susceptible and resistant groups, providing no support for a major role of genetic variation of antioxidant enzymes in the susceptibility to NIHL.
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| 24. |
- Carlsson, Per-Inge, 1959-, et al.
(author)
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Variabillity in noise susceptibility in a Swedish population : the role of 35delG mutation in the Connexin 26 (GJB2) gene
- 2004
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In: Audiological Medicine. - : Informa UK Limited. - 1651-386X .- 1651-3835. ; 2:2, s. 123-130
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Journal article (peer-reviewed)abstract
- Although it seems that genetic factors can influence individual susceptibility to noise, still very little is known about the genes or the mechanisms involved. The connexin 26 (Cx26) (GJB2) gene is of particular interest to study in relation to noise, since the gene encodes the gap junction protein Cx26. Noise has a metabolic and mechanical effect on the inner ear and may, therefore, interfere with gap junction channels. In order to investigate whether abnormally high susceptibility to noise induced hearing loss (NIHL) in humans is associated with the common 35delG mutation in the Cx26 gene, 1200 noise‐exposed workers were investigated in Sweden. Using a selection procedure based on audiometric analysis, noise exposure data and questionnaires, noise‐exposed workers were divided into two categories: noise susceptible and noise resistant. There was a correspondence in noise susceptibility between this noise‐exposed population and the international reference ISO Standard 1999. Blood samples were drawn from 245 highly selected male subjects (103 noise susceptible, 112 noise resistant and 30 randomized cases), and genomic DNA was analysed with respect to the Cx26 35delG mutation. The incidence of 35delG carriers among this cohort was determined by multiplex, allele‐specific PCR. Two of the 245 subjects (0.8% ‐ [95% confidence interval 0.1–2.9]) were found to be heterozygous carriers of the 35delG mutation, while the remaining 243 subjects were all non‐carriers. Both the heterozygous carriers were found in the noise susceptible group. Statistical evaluation of the results demonstrated no significant difference in carrier incidence between the noise susceptible and noise resistant individuals in our Swedish noise‐exposed population. In conclusion, there was no support for a major role of Cx26 35delG mutation in explaining the variability in noise susceptibility in this Swedish population.
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| 25. |
- Ekvall, Sara, et al.
(author)
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Co-Occurring SHOC2 and PTPN11 Mutations in a Patient With Severe/Complex Noonan Syndrome-Like Phenotype
- 2011
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In: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 155:6, s. 1217-1224
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Journal article (peer-reviewed)abstract
- Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A> G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c. 1226G>C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, cafe-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p. Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.
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