| 1. |
- Klar, Joakim, 1974-, et al.
(författare)
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Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage
- 2017
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function.
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| 2. |
- Jameel, Muhammad, et al.
(författare)
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A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
- 2014
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15, s. 133-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family.METHODS:We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI.RESULTS:We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease.CONCLUSION:This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.
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| 3. |
- Khan, Tahir Naeem, et al.
(författare)
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Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1l)
- 2012
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 13, s. 120-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anonychia/hyponychia congenita is a rare autosomal recessive developmental disorder characterized by the absence (anonychia) or hypoplasia (hyponuchia) of finger- and/or toenails frequently caused by mutations in the R-spondin 4 (RSPO4) gene. Methods: Three hypo/anonychia consanguineous Pakistani families were ascertained and genotyped using microsatellite markers spanning the RSPO4 locus on chromosome 20p13. Mutation screening of the RSPO4 gene was carried out by direct sequencing of the entire coding region and all intron-exon boundaries. Results: Mutations in the RSPO4 gene were identified in all families including a novel missense mutation c.178C>T (p.R60W) and two recurrent variants c.353G>A (p.C118Y) and c.3G>A (p.M1l). The c.3G>A variant was identified in unaffected family members and a control sample in a homozygous state. Conclusions: This study raises to 17 the number of known RSPO4 mutations and further expands the molecular repertoire causing hypo/anonychia. The c.353G>A emerges as a recurrent change with a possible founder effect in the Pakistani population. Our findings suggest that c.3G>A is not sufficient to cause the disorder and could be considered a polymorphism.
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| 4. |
- Nawaz, Sadia, et al.
(författare)
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Report of a recurrent mutation in ARS (component B) gene with severe Mal de Meleda in a large consanguineous Pakistani family
- 2011
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Ingår i: Pakistan journal of medical sciences print. - 1682-024X .- 1681-715X. ; 27:3, s. 686-689
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To characterize the disease causing mutation in a large consanguineous Pakistani family with severe Mat de Meleda (MDM) or keratosis palmoplantaris transgrediens, a rare autosomal recessive skin disorder. Methodology: Single nucleotide polymorphism (SNPs) genotyping was performed using the Gene Chip Mapping 250K array (Affymetrix). Homozygosity mapping and sorting of genomic regions were performed with dedicated software called AutoSNPa. Selected regions were further investigated by genotyping with microsatellite markers derived from known and novel pOlymorphic repeats. Two-point LOD score calculation was performed by using the MLINK of Fast link computer package. All three coding exons of ARS (component B) gene were amplified by PCR and sequenced. Conclusion: Sequencing of all the coding exons of ARS (component B) gene in the affected individuals revealed a recurrent missense mutation in exon 3 at base pair 256 from Guanine to Alanine (256G>A) and as a result the amino acid Glycine is replaced by Arginine at position 86 (G86R). This finding will facilitate control of affected MDM births in the Pakistani families.
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| 5. |
- Klar, Joakim, et al.
(författare)
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Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans
- 2015
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:9, s. 599-606
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Tidskriftsartikel (refereegranskat)abstract
- Background Keratosis pilaris atrophicans (KPA) is a group of rare genodermatoses characterised by perifollicular keratosis and inflammation that progresses to atrophy and scars of the facial skin. Keratosis pilaris of extensor areas of limbs is a common associated finding. Most cases with KPA are sporadic and no consistent inheritance pattern has been documented.Methods A large consanguineous Pakistani pedigree segregating autosomal recessive KPA of a mixed type was subject to autozygosity mapping and whole exome sequencing. Quantification of mRNA and protein levels was performed on fibroblasts from affected individuals. Cellular uptake of the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) ligand alpha 2-macroglobulin (alpha M-2) was quantified using fluorescence confocal microscopy.Results Genetic analyses identified a unique homozygous missense variant (K1245R) in the LRP1 in all affected family members. LRP1 encodes the LRP1, a multifunctional cell surface receptor with endocytic functions that belongs to the LDL receptor family. The LRP1 mRNA and LRP1 protein levels in fibroblasts of affected individuals were markedly reduced when compared with controls. Similarly, the LRP1-mediated cellular uptake of alpha M-2 was reduced in patient fibroblasts. Conclusions This is the first report on LRP1 as a pathogenic gene for autosomal recessive KPA and keratosis pilaris. The inflammatory characteristics of the KPA entity in our family suggest a link to the immune-regulatory functions of LRP1.
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