ABSTRACT
Nail Patella Syndrome (NPS; OMIM #161200) is a pleiotropic condition, with a classical clinical tetrad of involvement of the nails, knees, elbows and the presence of iliac horns. Kidney disease and glaucoma are now recognised as part of the syndrome. Fifty years ago, James Renwick chose NPS to develop methods of linkage analysis in humans and revealed the third linkage group identified in man--that between NPS and the ABO blood group loci. After a fallow period of some forty years, the gene mutated in NPS has been identified (LMX1B) and the condition serves as a model for understanding the complex relationships between disease loci, modifier genes and the resultant clinical phenotype.
Subject(s)
ABO Blood-Group System/history , Genetic Linkage , Nail-Patella Syndrome/history , ABO Blood-Group System/genetics , Amino Acid Sequence , Animals , History, 20th Century , History, 21st Century , Humans , Molecular Sequence Data , Nail-Patella Syndrome/geneticsABSTRACT
The genetic bases underlying the range and severity of phenotypes in Mendelian disorders is poorly understood; however, improvements in this area have the potential to facilitate analysis of oligogenic disorders. The nail dysplasia observed in Nail Patella Syndrome (NPS) was selected as a quantifiable variable within a Mendelian disorder, for which data could be readily obtained, to allow investigation of the genetic basis of variation. Analysis of SNP haplotypes across the LMX1B gene demonstrated association between the haplotype of the mutant allele and the variability in the nail score (p = 0.024). These results are in contrast to those obtained previously, which supported a modifying role for the wild-type allele. Since there is no evidence that particular mutations, or classes of mutation, are associated with the variation (p > 0.5), further work is required to identify the elements associated with the LMX1B gene that mediate phenotypic severity.
Subject(s)
Genetic Variation , Haplotypes/genetics , Homeodomain Proteins/genetics , Nail-Patella Syndrome/genetics , Nails, Malformed , Polymorphism, Single Nucleotide/genetics , DNA Mutational Analysis , Female , Genetic Linkage , Genotype , Humans , LIM-Homeodomain Proteins , Male , Mutation , Phenotype , Transcription FactorsABSTRACT
X inactivation is the mammalian method for X-chromosome dosage compensation, but some features of this developmental process vary among mammals. Such species variations provide insights into the essential components of the pathway. Tsix encodes a transcript antisense to the murine Xist transcript and is expressed in the mouse embryo only during the initial stages of X inactivation; it has been shown to play a role in imprinted X inactivation in the mouse placenta. We have identified its counterpart within the human X inactivation center (XIC). Human TSIX produces a >30-kb transcript that is expressed only in cells of fetal origin; it is expressed from human XIC transgenes in mouse embryonic stem cells and from human embryoid-body-derived cells, but not from human adult somatic cells. Differences in the structure of human and murine genes indicate that human TSIX was truncated during evolution. These differences could explain the fact that X inactivation is not imprinted in human placenta, and they raise questions about the role of TSIX in random X inactivation.
Subject(s)
Dosage Compensation, Genetic , RNA, Antisense/genetics , RNA, Untranslated/genetics , Transcription Factors/genetics , Aging/genetics , Animals , Cell Line , Embryo, Mammalian/metabolism , Evolution, Molecular , Fetus/metabolism , Genomic Imprinting/genetics , Humans , Mice , Molecular Sequence Data , Open Reading Frames/genetics , Placenta/metabolism , RNA, Antisense/analysis , RNA, Antisense/biosynthesis , RNA, Antisense/isolation & purification , RNA, Long Noncoding , RNA, Untranslated/analysis , RNA, Untranslated/biosynthesis , RNA, Untranslated/isolation & purification , Sequence Deletion/genetics , Sequence Homology, Nucleic Acid , Species Specificity , Stem Cells/metabolism , Transcription Initiation Site , Transcription, Genetic , Transgenes/geneticsABSTRACT
Nail patella syndrome (NPS) has been shown to result from loss of function mutations within the transcription factor LMX1B. In a large NPS family a 17 bp intronic deletion encompassing a consensus branchpoint sequence was observed to segregate with the NPS phenotype. RNA analysis demonstrated that deletion of the branchpoint sequence resulted in skipping of the downstream exon. A mechanism to explain this phenomenon is presented.
Subject(s)
Exons/genetics , Homeodomain Proteins/genetics , Nail-Patella Syndrome/genetics , Alternative Splicing , Amino Acid Sequence , Base Sequence , Cells, Cultured , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Humans , LIM-Homeodomain Proteins , Molecular Sequence Data , RNA/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Deletion , Transcription FactorsABSTRACT
Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.
