Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
All patients had biallelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C
Vitamin D may be essential for restricting the development and severity of allergic diseases and asthma, but a direct causal link between vitamin D deficiency and asthma has yet to be established. We have developed a ‘low dose’ model of allergic airway disease induced by intraperitoneal injection with ovalbumin (1 µg) and aluminium hydroxide (0.2 mg) in which characteristics of atopic asthma are recapitulated, including airway hyperresponsiveness, antigen-specific immunoglobulin type-E and lung inflammation. We assessed the effects of vitamin D deficiency throughout life (from conception until adulthood) on the severity of ovalbumin-induced allergic airway disease in vitamin D-replete and -deficient BALB/c mice using this model. Vitamin D had protective effects such that deficiency significantly enhanced eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male but not female mice. Vitamin D also suppressed the proliferation and T helper cell type-2 cytokine-secreting capacity of airway-draining lymph node cells from both male and female mice. Supplementation of initially vitamin D-deficient mice with vitamin D for four weeks returned serum 25-hydroxyvitamin D to levels observed in initially vitamin D-replete mice, and also suppressed eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male mice. Using generic 16 S rRNA primers, increased bacterial levels were detected in the lungs of initially vitamin D-deficient male mice, which were also reduced by vitamin D supplementation. These results indicate that vitamin D controls granulocyte levels in the bronchoalveolar lavage fluid in an allergen-sensitive manner, and may contribute towards the severity of asthma in a gender-specific fashion through regulation of respiratory bacteria.
Bonobos (Pan paniscus) inhabit regions south of the Congo River including all areas between its southerly tributaries. To investigate the genetic diversity and evolutionary relationship among bonobo populations, we sequenced mitochondrial DNA from 376 fecal samples collected in seven study populations located within the eastern and western limits of the species’ range. In 136 effective samples from different individuals (range: 7–37 per population), we distinguished 54 haplotypes in six clades (A1, A2, B1, B2, C, D), which included a newly identified clade (D). MtDNA haplotypes were regionally clustered; 83 percent of haplotypes were locality-specific. The distribution of haplotypes across populations and the genetic diversity within populations thus showed highly geographical patterns. Using population distance measures, seven populations were categorized in three clusters: the east, central, and west cohorts. Although further elucidation of historical changes in the geological setting is required, the geographical patterns of genetic diversity seem to be shaped by paleoenvironmental changes during the Pleistocene. The present day riverine barriers appeared to have a weak effect on gene flow among populations, except for the Lomami River, which separates the TL2 population from the others. The central cohort preserves a high genetic diversity, and two unique clades of haplotypes were found in the Wamba/Iyondji populations in the central cohort and in the TL2 population in the eastern cohort respectively. This knowledge may contribute to the planning of bonobo conservation.
In contrast to European countries, the overwhelming majority of dogs in the U.S. are neutered (including spaying), usually done before one year of age. Given the importance of gonadal hormones in growth and development, this cultural contrast invites an analysis of the multiple organ systems that may be adversely affected by neutering. Using a single breed-specific dataset, the objective was to examine the variables of gender and age at the time of neutering versus leaving dogs gonadally intact, on all diseases occurring with sufficient frequency for statistical analyses. Given its popularity and vulnerability to various cancers and joint disorders, the Golden Retriever was chosen for this study. Veterinary hospital records of 759 client-owned, intact and neutered female and male dogs, 1–8 years old, were examined for diagnoses of hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and mast cell tumor (MCT). Patients were classified as intact, or neutered early (<12 mo) or late (≥12 mo). Statistical analyses involved survival analyses and incidence rate comparisons. Outcomes at the 5 percent level of significance are reported. Of early-neutered males, 10 percent were diagnosed with HD, double the occurrence in intact males. There were no cases of CCL diagnosed in intact males or females, but in early-neutered males and females the occurrences were 5 percent and 8 percent, respectively. Almost 10 percent of early-neutered males were diagnosed with LSA, 3 times more than intact males. The percentage of HSA cases in late-neutered females (about 8 percent) was 4 times more than intact and early-neutered females. There were no cases of MCT in intact females, but the occurrence was nearly 6 percent in late-neutered females. The results have health implications for Golden Retriever companion and service dogs, and for oncologists using dogs as models of cancers that occur in humans.
In June 2007, a previously undescribed monkey known locally as “lesula” was found in the forests of the middle Lomami Basin in central Democratic Republic of Congo (DRC). We describe this new species as Cercopithecus lomamiensis sp. nov., and provide data on its distribution, morphology, genetics, ecology and behavior. C. lomamiensis is restricted to the lowland rain forests of central DRC between the middle Lomami and the upper Tshuapa Rivers. Morphological and molecular data confirm that C. lomamiensis is distinct from its nearest congener, C. hamlyni, from which it is separated geographically by both the Congo (Lualaba) and the Lomami Rivers. C. lomamiensis, like C. hamlyni, is semi-terrestrial with a diet containing terrestrial herbaceous vegetation. The discovery of C. lomamiensis highlights the biogeographic significance and importance for conservation of central Congo’s interfluvial TL2 region, defined from the upper Tshuapa River through the Lomami Basin to the Congo (Lualaba) River. The TL2 region has been found to contain a high diversity of anthropoid primates including three forms, in addition to C. lomamiensis, that are endemic to the area. We recommend the common name, lesula, for this new species, as it is the vernacular name used over most of its known range.
Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified.
Enamel; Amelogenesis imperfecta; Phenotype; Genotype; Gene; Mutation
The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus.
C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase.
Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species.
Hypothermia, defined as a core body temperature less than 36°C (96.8°F), is a relatively common occurrence in the unwarmed surgical patient. A mild degree of perioperative hypothermia can be associated with significant morbidity and mortality. A threefold increase in the frequency of surgical site infections is reported in colorectal surgery patients who experience perioperative hypothermia. As part of the Surgical Care Improvement Project, guidelines aim to decrease the incidence of this complication.
We review the physiology of temperature regulation, mechanisms of hypothermia, effects of anesthetics on thermoregulation, and consequences of hypothermia and summarize recent recommendations for maintaining perioperative normothermia.
Evidence suggests that prewarming for a minimum of 30 minutes may reduce the risk of subsequent hypothermia.
Monitoring of body temperature and avoidance of unintended perioperative hypothermia through active and passive warming measures are the keys to preventing its complications.
Hypothermia; perioperative; prewarming; thermoregulation
FAM83H gene mutations are associated with autosomal-dominant hypocalcified amelogenesis imperfecta (ADHCAI), which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tested the hypothesis that there are phenotype and genotype associations in families with FAM83H-associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological, and biochemical studies, and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified, including two 2-bp-deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 or fewer amino acids presented a generalized ADHCAI phenotype, while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows that unique phenotypes are associated with specific FAM83H mutations.
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
Hyaluronidases degrade hyaluronic acid, a major polysaccharide of the extracellular matrix of tissues, and are considered important for virulence in a number of Gram-positive and -negative bacteria. The purpose of the present study was to determine the prevalence of hyaluronidase among clinical strains of Staphylococcus aureus and among other Staphylococcus species. Spent media and chromosomal DNA were assessed for hyaluronidase activity and the absence or presence of a hyaluronidase gene (hysA) by Southern analysis, respectively. All S. aureus strains examined exhibited at least one hybridizing band (half of the strains exhibited two or more hybridizing bands) when probed for hysA and all but three of these strains produced hyaluronidase. In contrast, none of the type strains of 19 other species exhibited either hyaluronidase activity or hybridizing bands when probed for hysA. These data support the hypothesis that among members of the Staphylococcus genus only strains of S. aureus possess the enzyme hyaluronidase. This would suggest that hyaluronidase represents yet another potential virulence factor employed by S. aureus to cause disease and may represent a diagnostically important characteristic for distinguishing S. aureus from other members of this genus.
Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31-q32 at or near the platelet derived growth factor-C (PDGF-C) locus. The mouse pdgfc−/− knockout demonstrates that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1,048 multiplex CL/P families and 1,000 case-control samples from multiple geographic origins. No coding region mutations were identified, but a novel -986 C>T SNP (rs28999109) was significantly associated with CL/P (p=0.01) in cases from Chinese families yielding evidence of linkage to 4q31-q32. Significant or near significant association was also seen for this and several other PDGF-C SNPs in families from the US, Spain, India, Turkey, China, and Colombia, while no association was seen in families from the Philippines, Guatemala, and case-controls from Brazil. The -986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs demonstrate the -986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.
PDGF-C; SNP; CL/P; promoter activity
FAM83H gene mutations are associated with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) which is typically characterized by enamel having normal thickness and a markedly decreased mineral content. This study tests the hypothesis that there are phenotype and genotype associations in families with FAM83H associated ADHCAI. Seven families segregating ADHCAI (147 individuals) were evaluated. Phenotyping included clinical, radiographic, histological and biochemical studies and genotyping was by mutational analysis. Multiple novel FAM83H mutations were identified including two 2 bp deletion mutations, the first non-nonsense mutations identified. Craniofacial deviation from normal was more prevalent in the affected individuals. Affected individuals having truncating FAMH3H mutations of 677 amino acids or less presented generalized ADHCAI phenotype while those having mutations capable of producing a protein of at least 694 amino acids had a unique and previously unreported phenotype affecting primarily the cervical enamel. This investigation shows unique phenotypes are associated with specific FAM83H mutations.
enamel; FAM83H; amelogenesis imperfecta; hypocalcified; phenotype; craniofacial
The amelogenesis imperfectas (AI) are caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM, and KLK4 genes were identified. The majority of human mutations for genes coding enamel non-proteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia compared with humans having MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide powerful models for understanding the pathogenesis of these conditions.
enamel; amelogenesis imperfecta; mouse; human; gene; mutation
Five mutations in the ENAM gene have been found to cause hypoplastic amelogenesis imperfecta (AI), with phenotypes ranging from localized enamel pitting in carriers to severe hypoplastic AI. To determine the generality of ENAM mutations in hypoplastic AI, we sequenced the ENAM gene in ten Turkish families segregating autosomal hypoplastic AI. In two families, ENAM mutations were found. A novel nonsense mutation (g.12663C>A; p.S246X) was identified in one family segregating local hypoplastic AI as a dominant trait. Affected individuals in a second family segregating autosomal-recessive AI were compound heterozygotes for a novel insertion mutation (g.12946_12947insAGTCAGTACCAGTACTGT GTC) and a previously described insertion (g.13185_13186insAG) mutation. Heterozygous carriers of either insertion had a localized enamel-pitting phenotype. These findings substantiate that enamel phenotypes of ENAM mutations may be dose-dependent, with generalized hypoplastic AI segregating as a recessive trait and localized enamel pitting segregating as a dominant trait.
amelogenesis imperfecta; enamel; enamel pitting; gene dosage; enamelin
Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31–q32 at or near the platelet-derived growth factor-C (PDGF-C) locus. The mouse Pdgfc−/− knockout shows that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1048 multiplex CL/P families and 1000 case–control samples from multiple geographic origins. No coding region mutations were identified, but a novel −986 C>T SNP (rs28999109) was significantly associated with CL/P (P=0.01) in cases from Chinese families yielding evidence of linkage to 4q31–q32. Significant or near-significant association was also seen for this and several other PDGF-C SNPs in families from the United States, Spain, India, Turkey, China, and Colombia, whereas no association was seen in families from the Philippines, and Guatemala, and case–controls from Brazil. The −986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs show that the −986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.
PDGF-C; SNP; CL/P; promoter activity
A 4 base-pair deletion mutation in the Distal-Less 3 (DLX3) gene is etiologic for Tricho-Dento-Osseous syndrome (TDO). A cardinal feature of TDO is an increased thickness and density of bone. We tested the effects of the DLX3 gene mutation responsible for TDO on the osteoblastic differentiation of preosteoblastic MC3T3E1 cells and multipontent mesenchymal C2C12 cells. Differential expression analysis of C2C12 cells transfected with wild type DLX3 or mutant DLX3 was performed and desmin gene expression, an early myoblastic differentiation marker in mesenchymal cells, was evaluated by RT-PCR, western blot analysis, and desmin promoter transcriptional activity. Transfection of wild type DLX3 into MC3T3E1 and C2C12 cells increased alkaline phosphatase-2 activity, mineral deposition, and promoter activities of the osteocalcin and type1 collagen genes compared to empty vector transfected cells. Transfection of mutant DLX3 into these cells further enhanced alkaline phosphatase activity, mineral deposition, and osteocalcin promoter activities, but did not further enhance type 1 collagen promoter activity. Transfection of mutant DLX3 into C2C12 cells markedly down regulated desmin gene expression, and protein expression of desmin and MyoD, while increasing protein expression of osterix and Runx2. These results demonstrate that the DLX3 deletion mutation associated with TDO enhances mesenchymal cell differentiation to an osteoblastic lineage rather than a myoblastic lineage by changing the fate of mesenchymal cells. This DLX3 mutation also accelerates the differentiation of osteoprogenitor cells to osteoblasts at later stages of osteogenesis.
Distal-Less 3; Tricho-Dento-Osseous syndrome; Osteoblast differentiation; Osteocalcin; Collagen
Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders due to mutations in DSPP. Typically, the phenotype breeds true within a family. Recently, two reports showed that three different net -1 bp frameshift mutations early in DSPP's repeat domain caused DD whereas six, more 3′ frameshift mutations, were associated with DGI. Here we identify a DD kindred with a novel -1 bp frameshift (c.3141delC) that falls within the portion of the DSPP repeat domain previously associated solely with the DGI phenotype. This new frameshift mutation shows that overlapping DSPP mutations can give rise to either DGI or DD phenotypes. Furthermore, the consistent kindred presentation of the DD or DGI phenotype appears to be dependent on an as yet undescribed genetic modifier closely linked to DSPP.
DSPP; dentinogenesis imperfecta; dentin dysplasia; DPP
Amelogenesis imperfecta (AI) is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.
Enamel; Amelogenesis imperfecta; Mouse; Human; Gene; Mutation
The Amelogenesis Imperfecta (AI) are a group of clinically and genetically heterogeneous disorders that affect enamel formation. To date, mutations in 4 genes have been reported in various types of AI. Mutations in the genes encoding the 2 enamel proteases, matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4), have each been reported in a single family segregating autosomal-recessive hypomaturation AI. To determine the frequency of mutations in these genes, we analyzed 15 Turkish probands with autosomal-recessive hypo-maturation AI for MMP20 and KLK4 gene mutations. No KLK4 mutations were found. A novel MMP20 mutation (g.16250T>A) was found in one family. This missense mutation changed the conserved active-site His226 residue of the zinc catalytic domain to Gln (p.H226Q). Zymogram analysis demonstrated that this missense mutation abolished MMP20 proteolytic activity. No MMP20 mutations were found in the remaining 14 probands, underscoring the genetic heterogeneity of hypomaturation AI.
amelogenesis imperfecta; MMP20; proteolytic activity; hypomaturation; enamelysin
Amelogenesis imperfecta (AI) is a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Mutations in several enamel proteins and proteinases have been associated with AI. The object of this study was to evaluate evidence of etiology for the six major candidate gene loci in two Brazilian families with AI. Genomic DNA was obtained from family members and all exons and exon-intron boundaries of the ENAM, AMBN, AMELX, MMP20, KLK4 and Amelotin gene were amplified and sequenced. Each family was also evaluated for linkage to chromosome regions known to contain genes important in enamel development. The present study indicates that the AI in these two families is not caused by any of the known loci for AI or any of the major candidate genes proposed in the literature. These findings indicate extensive genetic heterogeneity for non-syndromic AI.
Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic.
Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2.
Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family).
Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2.
Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
We describe a mutation and haplotype analysis of Papillon-Lefèvre syndrome probands that provides evidence of a founder effect for four separate cathepsin C mutations. A total of 25 different cathepsin C mutations have been reported in 32 families with Papillon-Lefèvre syndrome (PLS) and associated conditions. A characteristic of these findings is the diversity of different cathepsin C mutations that have been identified. To evaluate the generality of cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. Sequence analysis identified two cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presence of the R272P mutation in probands from these four Saudi families makes this the most frequently reported cathepsin C mutation. To distinguish between the presence of a possible founder effect or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval containing the cathepsin C gene. Results of haplotype analysis for genetic polymorphisms within and flanking the cathepsin C gene are consistent with inheritance of the R272P mutation "identical by descent" from a common ancestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritance of each of these mutations from common ancestors. These data suggest that four of the more frequently reported cathepsin C mutations have been inherited from common ancestors and provide the first direct evidence for a founder effect for cathepsin C gene mutations in PLS. Identification of these six short tandem repeat polymorphisms that span the cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of cathepsin C mutations in additional PLS families.
Keywords: Papillon-Lefèvre syndrome; cathepsin C; founder effect; chromosome 11q14