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1.
Diabet Med ; 32(6): 834-8, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25546232

ABSTRACT

AIMS: To investigate the clinical relevance and cost-effectiveness of human leukocyte antigen (HLA)-genotyping in the Netherlands as a screening tool for the development of coeliac disease in children with Type 1 diabetes mellitus. METHODS: A retrospective analysis was performed in 110 children with Type 1 diabetes mellitus diagnosed between January 1996 and January 2013. All children were screened for coeliac disease using coeliac disease-specific antibodies and HLA genotyping was performed in all children. RESULTS: One hundred and ten children were screened for coeliac disease, and coeliac disease could be confirmed in seven. Eighty-six per cent of the children with Type 1 diabetes mellitus had one of the variants of HLA-DQ2.5 and DQ8. HLA genotypes observed in children with Type 1 diabetes mellitus children and coeliac disease were heterozygote DQ2.5, homozygote DQ2.5 and heterozygote DQ2.5/DQ8. HLA genotyping in coeliac disease screening in children with Type 1 diabetes mellitus is more expensive than screening for coeliac disease with antibodies alone (€326 vs. €182 per child). CONCLUSIONS: The risk of coeliac disease development in children with Type 1 diabetes mellitus is increased when they are heterozygote DQ2.5/DQ8, homozygote or heterozygote DQ2.5. The implementation of HLA genotyping as a first-line screening tool has to be reconsidered because it is not distinctive or cost-effective.


Subject(s)
Celiac Disease/diagnosis , Diabetes Mellitus, Type 1/genetics , Genotyping Techniques/economics , HLA Antigens/genetics , Mass Screening/economics , Celiac Disease/economics , Celiac Disease/epidemiology , Celiac Disease/genetics , Child , Child, Preschool , Cost-Benefit Analysis , Diabetes Mellitus, Type 1/economics , Diabetes Mellitus, Type 1/epidemiology , Female , Genetic Predisposition to Disease , Genetic Testing/economics , Genetic Testing/methods , Genotyping Techniques/methods , HLA-DQ Antigens/genetics , Humans , Male , Mass Screening/methods , Netherlands/epidemiology
2.
J Dent Res ; 88(6): 569-74, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19587164

ABSTRACT

Sclerostin is an inhibitor of bone formation expressed by osteocytes. We hypothesized that sclerostin is expressed by cells of the same origin and also embedded within mineralized matrices. In this study, we analyzed (a) sclerostin expression using immunohistochemistry, (b) whether the genomic defect in individuals with van Buchem disease (VBD) was associated with the absence of sclerostin expression, and (c) whether this was associated with hypercementosis. Sclerostin was expressed by cementocytes in mouse and human teeth and by mineralized hypertrophic chondrocytes in the human growth plate. In individuals with VBD, sclerostin expression was absent or strongly decreased in osteocytes and cementocytes. This was associated with increased bone formation, but no overt changes in cementum thickness. In conclusion, sclerostin is expressed by all 3 terminally differentiated cell types embedded within mineralized matrices: osteocytes, cementocytes, and hypertrophic chondrocytes.


Subject(s)
Bone Morphogenetic Proteins/biosynthesis , Bone Morphogenetic Proteins/deficiency , Osteocytes/metabolism , Osteosclerosis/metabolism , Adaptor Proteins, Signal Transducing , Adolescent , Adult , Animals , Child , Chondrocytes/metabolism , Dental Cementum/metabolism , Female , Genetic Markers , Growth Plate/metabolism , Humans , Jaw Abnormalities/etiology , Male , Malocclusion/etiology , Mice , Middle Aged , Osteosclerosis/complications , Osteosclerosis/diagnostic imaging , Radiography, Panoramic , Tooth Abnormalities/etiology , Young Adult
3.
Calcif Tissue Int ; 81(6): 421-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18058054

ABSTRACT

PURPOSE: To investigate the impact of the Ala1330Val (rs3736228, exon 18) and Val667Met (rs4988321, exon 9) polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene on peak bone mass in young men. METHODS: The Odense Androgen Study (OAS) is a population-based study comprising 783 Caucasian men aged 20-30 years. Genotyping was performed using real-time polymerase chain reaction (PCR) or fluorescence polarization. Bone mineral density (BMD) measurements were performed using dual-energy X-ray absorptiometry. RESULTS: The CC, CT, and TT genotypes in Ala1330Val were found in 75.6%, 21.8%, and 2.6% of the participants, respectively. Similarly, the GG, GA, and AA genotypes of Val667Met were found in 89.7%, 9.8%, and 0.5%, respectively. For the Ala1330Val polymorphism, no significant differences between the genotypes were found regarding BMD in the overall study population. However, when analysis was restricted to non-sedentary men (n = 589), a significant association between the number of T-alleles and BMD in the spine and whole body were found. Each copy of the T-allele changed the Z-score of the spine by (median and 95% confidence interval) -0.21 [95% CI: -0.40; -0.03] (p < 0.02). Analysis suggested an association between the AA genotype in the Val667Met polymorphism and increased body height and decreased BMD of the femoral neck; however, no significant gene-dose effect of the A-allele could be demonstrated in the whole population. When the analysis was restricted to non-sedentary subjects, however, each number of A-alleles was associated with a change in Z-score of -0.26 [95% CI: -0.51; -0.01] (p = 0.04). No further significant results emerged with haplotype analysis. CONCLUSION: The Ala1330Val and Val667Met polymorphisms in the LRP5 gene are significantly associated with peak bone mass in physically active men.


Subject(s)
Bone Density/genetics , LDL-Receptor Related Proteins/genetics , Polymorphism, Single Nucleotide , Absorptiometry, Photon , Alanine/genetics , Androgens/metabolism , Gene Frequency , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Life Style , Low Density Lipoprotein Receptor-Related Protein-5 , Male , Methionine/genetics , Valine/genetics , White People
5.
Ned Tijdschr Geneeskd ; 150(37): 2009-12, 2006 Sep 16.
Article in Dutch | MEDLINE | ID: mdl-17058454

ABSTRACT

Two girls developed symptoms of wheezing which started shortly after birth. The symptoms did not respond to bronchodilators. At the age of 5 months, the first infant developed severe respiratory distress with decreased left-sided breathing sounds on auscultation. The chest X-ray showed left-sided hyperinflation. Bronchoscopy revealed isolated malacia of the left main stem bronchus. The second patient, who had a history ofcor vitium, was referred to a paediatric pulmonologist in an academic hospital for chronic coughing and wheezing. Bronchoscopy and CT angiogram, performed at the age of 14 months, revealed tracheal malacia due to compression from a right descending aortic arch. Broncho- and tracheomalacia are disorders which may rarely result in severe respiratory distress. These disorders should be considered when unexplained symptoms of wheezing or coughing are present in young infants, especially if the symptoms start shortly after birth and persist without signs of viral infection.


Subject(s)
Bronchi/abnormalities , Bronchial Diseases/congenital , Respiratory Insufficiency/etiology , Respiratory Sounds/etiology , Trachea/abnormalities , Tracheal Diseases/congenital , Bronchial Diseases/diagnosis , Bronchoscopy/methods , Congenital Abnormalities/diagnosis , Female , Humans , Infant , Infant, Newborn , Respiratory Insufficiency/diagnosis , Tracheal Diseases/diagnosis
6.
Clin Exp Allergy ; 36(1): 40-3, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16393264

ABSTRACT

OBJECTIVE: To investigate the association between adenoidectomy and/or tonsillectomy in childhood and asthma, allergic rhinitis (AR), and eczema in adolescence. METHODS: Longitudinal birth cohort study of 1328 members born in the city of Nijmegen. Information on ear-nose-throat surgery was documented at 2, 4, and 8 years of age. In 1055 cohort members the incidence of asthma, AR, and eczema at 21 years of age was determined using the International Study of Asthma and Allergic disease in Childhood Core Questionnaire. To analyse the association between adenoidectomy and/or tonsillectomy in childhood and asthma, AR, and eczema at age 21 years, relative risks (RR) were calculated. RESULTS: Six hundred and ninety-three (66%) members completed the questionnaire at age 21 years, of whom 104 (15%) had undergone adenoidectomy and/or tonsillectomy and 262 (38%) reported atopic disease. Children who underwent adenoidectomy and/or tonsillectomy before the age of 8 years were not more likely to develop asthma, AR, or eczema at the age of 21 years than children who did not; RR 0.93 (95% confidence limits (CL) 0.52-1.64), RR 0.94 (CL 0.68-1.30), and RR 1.00 (CL 0.59-1.68), respectively. CONCLUSIONS: Our data show no association between adenoidectomy and/or tonsillectomy in childhood and the incidence of atopic disease in young adults.


Subject(s)
Adenoidectomy , Hypersensitivity/etiology , Tonsillectomy , Adult , Asthma/etiology , Asthma/immunology , Child , Child, Preschool , Eczema/etiology , Eczema/immunology , Female , Humans , Hypersensitivity/immunology , Longitudinal Studies , Male , Rhinitis/etiology , Rhinitis/immunology , Risk Assessment , Treatment Outcome
7.
Clin Exp Allergy ; 36(2): 198-203, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16433857

ABSTRACT

BACKGROUND: Children of large families and those attending day care are at increased risk of respiratory tract infections, which in turn may protect against the development of allergic disease. Longitudinal studies investigating these associations beyond childhood are, however, scarce. OBJECTIVE: To investigate the association between childhood recurrent upper respiratory tract infections (URTI) and asthma, allergic rhinitis (AR) and eczema in adulthood. METHODS: A birth cohort of 1055 members followed prospectively from the ages of 2 to 21 years. Detailed information on URTI between the ages of 2 and 4 years was collected at 3 monthly intervals in a standardized interview. At the age of 8 years, a parental questionnaire regarding URTI between the ages of 4 and 8 years was used. The incidence of asthma and atopic disease at the age of 21 years was determined using a standardized questionnaire. RESULTS: Of the original cohort, 693 (66%) members completed the questionnaire. Children who experienced recurrent URTI before the age of 2 years, between the ages of 2-4 years and between ages of 4 and 8 years were not less likely to have asthma at 21 years of age than children who did not experience recurrent URTI, relative risk (RR) 0.97 (95% confidence interval (CI) 0.65-1.46), RR 1.45 (CI 0.95-2.21) and RR 1.51 (CI 0.97-2.36), respectively. Neither were recurrent URTI associated with a decreased risk of AR, nor eczema at the age of 21 years. CONCLUSIONS: Recurrent URTI in childhood did not reduce the risk of atopic disease in young adulthood.


Subject(s)
Hypersensitivity/etiology , Respiratory Tract Infections/complications , Adolescent , Adult , Asthma/etiology , Asthma/immunology , Child , Child Day Care Centers , Child, Preschool , Confidence Intervals , Eczema/etiology , Eczema/immunology , Family Characteristics , Female , Humans , Hypersensitivity/immunology , Incidence , Male , Prospective Studies , Recurrence , Respiratory Tract Infections/immunology , Risk
8.
Calcif Tissue Int ; 77(5): 263-74, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16307387

ABSTRACT

The osteopetroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density due to a defect in osteoclastic bone resorption. In humans, several types can be distinguished and a classification has been made based on their mode of inheritance, age of onset, severity, and associated clinical symptoms. The best-known forms of osteopetrosis are the malignant and intermediate autosomal recessive forms and the milder autosomal dominant subtypes. In addition to these forms, a restricted number of cases have been reported in which additional clinical features unrelated to the increased bone mass occur. During the last years, molecular genetic studies have resulted in the identification of several disease-causing gene mutations. Thus far, all genes associated with a human osteopetrosis encode proteins that participate in the functioning of the differentiated osteoclast. This contributed substantially to the understanding of osteoclast functioning and the pathogenesis of the human osteopetroses and will provide deeper insights into the molecular pathways involved in other bone pathologies, including osteoporosis.


Subject(s)
Osteopetrosis , Bone Density/physiology , Bone Resorption/genetics , Bone Resorption/physiopathology , Humans , Osteoclasts/physiology , Osteopetrosis/genetics , Osteopetrosis/physiopathology
9.
J Musculoskelet Neuronal Interact ; 4(2): 139-42, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15615113

ABSTRACT

Genetic studies recently unraveled the genetic cause of sclerosteosis, a rare skeletal dysplasia characterized by a generalized increase in bone mass. Different loss-of-function mutations were identified in SOST, a gene with no homology to any known gene. This SOST gene is also involved in the pathogenesis of van Buchem disease, a disorder closely resembling sclerosteosis, since a 52-kb deletion located downstream of SOST is found in patients diagnosed with this condition. Molecular studies showed a very restricted expression pattern of SOST and its gene product, sclerostin, with areas in the bone tissue, more precisely in cells of the osteoblast lineage, being the major sites of expression. Sclerostin is a secreted protein with a cysteine knot motif. In vitro studies demonstrated that sclerostin acts as a modulator of BMP signaling by binding to different members of the BMP growth factor family and acting on downstream BMP signal transduction events. The important function of sclerostin in bone metabolism has also been proven in vivo by the osteopenic phenotype of transgenic mice overexpressing SOST in bone. The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.


Subject(s)
Bone Morphogenetic Proteins/genetics , Bone Morphogenetic Proteins/metabolism , Genetic Markers/genetics , Osteosclerosis/genetics , Osteosclerosis/metabolism , Adaptor Proteins, Signal Transducing , Animals , Bone and Bones/metabolism , Bone and Bones/physiopathology , Humans , Osteosclerosis/physiopathology
10.
Bone ; 31(4): 515-9, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12398949

ABSTRACT

Osteoporosis is a common disease characterized by a decrease in bone mass, architectural deterioration of the bone tissue, and an increased risk of fracture. The condition is under strong genetic control, involving a large variety of gene products, but to date the genes responsible remain poorly defined. Although population-based studies have identified polymorphisms in several candidate genes that are associated with bone mineral density (BMD), these account for only a small proportion of the population variance in bone mass. In this study, we looked for evidence of an allelic association between polymorphisms in the SOST gene and BMD. This gene was analyzed because loss-of-function mutations in SOST cause sclerosteosis, a sclerosing bone dysplasia associated with increased bone mass due to increased bone formation. We identified 26 different polymorphisms in the SOST gene and selected 5 of these for association analysis in a case-control study of 619 women with either high or low BMD, drawn from a random population-based survey of 5119 perimenopausal white women. The high BMD group comprised 326 women in whom lumbar spine BMD values adjusted for age, height, and weight were in the highest 16% of the population distribution, and the low BMD group comprised 293 women in whom BMD values were in the lowest 16% of the population distribution. The distribution of genotypes and alleles for each Single Nucleotide Polymorphism (SNP) examined did not differ in the low and high BMD groups. We conclude that, in this population, common allelic variations in the SOST gene do not contribute significantly to the regulation of high or low BMD.


Subject(s)
Bone Density/genetics , Bone Morphogenetic Proteins , Climacteric , Genetic Markers/genetics , Polymorphism, Genetic , Proteins/genetics , Adaptor Proteins, Signal Transducing , Female , Humans , Middle Aged
11.
J Med Genet ; 39(2): 91-7, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11836356

ABSTRACT

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.


Subject(s)
Bone Morphogenetic Proteins , Osteochondrodysplasias/genetics , Proteins/genetics , Sequence Deletion/genetics , Adaptor Proteins, Signal Transducing , Aged , Base Sequence , Consanguinity , DNA Mutational Analysis , Female , Genetic Linkage/genetics , Genetic Markers/genetics , Humans , Male , Molecular Sequence Data
12.
Eur J Radiol ; 40(3): 198-207, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11731208

ABSTRACT

Bone mineral density (BMD) is a quantitative trait for which the heritability of the variance is estimated to be up to 80%, based on epidemiological and twin studies. Further illustration of the involvement of genetic factors in bone homeostasis, is the existence of an extended group of genetic conditions associated with an abnormal bone density. The group of conditions with increased bone density has long been poorly studied and understood at the molecular genetic level but recently, thanks to recent developments in molecular genetics and genomics, for some of them major breakthroughs have been made. These findings will make the molecular analysis of such patients an additional tool in diagnostics and in genetic counseling. However, the initial identification of affected patients is still largely dependent upon recognition of clinical and radiological stigmata of the disease. Therefore, in this overview of sclerosing bone dysplasias, the classical clinical and radiological signs of this group of disorders will be discussed along with the new molecular insights.


Subject(s)
Bone Diseases, Developmental/diagnosis , Camurati-Engelmann Syndrome/diagnostic imaging , Bone Density , Bone Diseases, Developmental/diagnostic imaging , Bone Diseases, Developmental/genetics , Humans , Melorheostosis/diagnosis , Osteopetrosis/diagnosis , Osteopetrosis/genetics , Osteopoikilosis/diagnostic imaging , Radiography
13.
Hum Mol Genet ; 10(5): 537-43, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11181578

ABSTRACT

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.


Subject(s)
Bone Density , Bone Morphogenetic Proteins , Genetic Markers , Osteochondrodysplasias/physiopathology , Adaptor Proteins, Signal Transducing , Amino Acid Sequence , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 17 , DNA Mutational Analysis , DNA, Complementary , Genetic Linkage , Humans , Molecular Sequence Data , Osteochondrodysplasias/genetics , Protein Conformation , Proteins/genetics , RNA, Messenger/genetics , Sequence Homology, Amino Acid
14.
Hum Genet ; 107(1): 7-11, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10982027

ABSTRACT

DFNA10 originally was mapped to the long arm of chromosome 6 in a large American family segregating for autosomal dominant progressive nonsyndromic hearing impairment. By extending this American family, we have reduced the original DFNA10 candidate region from 13 cM to 3.7 cM. We also report a Belgian family with autosomal dominant nonsyndromic hearing impairment linked to DFNA10 and a Norwegian family with the same condition in which linkage is suggestive, although maximum lod scores are only 2.5. The hearing phenotype in all three DFNA10 families is similar, with losses beginning in the middle frequencies and involving the low and high frequencies later in life.


Subject(s)
Deafness/genetics , Genetic Linkage , Audiometry , Chromosome Mapping , Chromosomes, Human, Pair 6 , Expressed Sequence Tags , Family Health , Female , Genetic Markers , Haplotypes , Humans , Lod Score , Male , Pedigree , Phenotype
15.
Eur Radiol ; 10(9): 1423-33, 2000.
Article in English | MEDLINE | ID: mdl-10997431

ABSTRACT

Although knowledge of basic genetics in the field of sclerosing bone dysplasias is progressing, the radiologist still plays a pivotal role in the diagnosis of this relatively poorly understood group of disorders. Based on a target site approach, these anomalies are classified into three groups. Within each group, further differentiation can be made by distinctive clinical findings and by mode of inheritance: (a) dysplasias of endochondral bone formation: osteopetrosis (Albers-Schönberg disease), pycnodysostosis, enostosis, osteopoikilosis, osteopathia striata (Voorhoeve disease); (b) dysplasias of intramembranous bone formation: progressive diaphyseal dysplasia (Camurati-Engelmann disease) and variants, hyperostosis corticalis generalisata (Van Buchem disease) and variants; and (c) mixed sclerosing dysplasias: melorheostosis (Leri disease) and overlap syndromes.


Subject(s)
Bone Diseases, Developmental/diagnostic imaging , Bone Diseases, Developmental/classification , Bone Diseases, Developmental/genetics , Bone Diseases, Developmental/pathology , Humans , Radiography , Sclerosis
16.
Eur Neurol ; 42(2): 109-15, 1999.
Article in English | MEDLINE | ID: mdl-10473983

ABSTRACT

Fourteen patients with classical features of Friedreich's ataxia (FRDA) were examined. The clinical diagnosis of FRDA was afterwards confirmed in all patients by the appropriate DNA investigation which showed markedly increased amounts of GAA repeats on both alleles of the frataxin gene. None of our patients presented with atypical features such as late-onset FRDA, FRDA with retained deep tendon reflexes or with a very slow course. Five of them are not yet confined to a wheelchair. But for 1 patient who died at age 36 years and had the largest number of GAA repeats on both alleles, there was no significant correlation between number of repeats in the shortest allele, age at onset, age at wheelchair dependence, duration of the disease and main clinical signs. All patients but 3 had between 500 and 1,050 GAA repeats. The 3 patients with, respectively, 400, 450 and 500 repeats on the shortest allele had a clinical course comparable to the other patients. Even in the case of variations in the number of repeats in the same sibship, there were only modest differences between the siblings concerning age at onset of the disease, symptoms and signs and age at wheelchair dependence. There were no qualitative differences in the main clinical features and laboratory investigations in the full-blown phase of the disorder. Molecular biology has become a major element in the diagnosis of FRDA. DNA testing for FRDA should be applied to every case of idiopathic autosomal recessive or sporadic ataxia. However, the clinical features of FRDA remain fully characteristic in many patients and keep their diagnostic value.


Subject(s)
Friedreich Ataxia/diagnosis , Friedreich Ataxia/genetics , Iron-Binding Proteins , Adolescent , Adult , Age of Onset , Female , Friedreich Ataxia/enzymology , Genotype , Humans , Male , Phenotype , Phosphotransferases (Alcohol Group Acceptor)/genetics , Trinucleotide Repeat Expansion , Trinucleotide Repeats/genetics , Frataxin
17.
Am J Hum Genet ; 64(6): 1661-9, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10330353

ABSTRACT

Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis.


Subject(s)
Bone Diseases, Developmental/genetics , Chromosomes, Human, Pair 17 , Adult , Aged , Bone Diseases, Developmental/diagnostic imaging , Chromosome Mapping , Female , Genetic Linkage , Genotype , Humans , Male , Pedigree , Tomography, X-Ray Computed
18.
J Bone Miner Res ; 13(6): 911-7, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9626621

ABSTRACT

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.


Subject(s)
Chromosome Aberrations/genetics , Chromosomes, Human, 21-22 and Y/genetics , Chromosomes, Human, Pair 18/genetics , Osteitis Deformans/genetics , Chromosome Disorders , Genetic Markers/genetics , Genetic Predisposition to Disease , Humans , Japan , Microsatellite Repeats , Pedigree , Spain , United Kingdom
19.
Am J Hum Genet ; 62(2): 391-9, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9463328

ABSTRACT

Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?239100]) is an autosomal recessive disorder characterized by hyperostosis of the skull, mandible, clavicles, ribs, and diaphyseal cortices of the long bones. The most striking clinical features are the enlargement of the jaw and the thickness of the skull, which may lead to facial nerve palsy, hearing loss, and optic atrophy. Increased formation, by osteoblasts, of qualitatively normal bone has been proposed as the underlying pathological mechanism, but the molecular defect is unknown. We studied 11 van Buchem patients and their highly inbred family, who live in The Netherlands in a small ethnic isolate, that had a common ancestor approximately 9 generations ago. A genomewide search with highly polymorphic microsatellite markers showed linkage to marker D17S1299 on chromosome 17q12-21 (maximum LOD score of 8.82 at a recombination fraction [straight theta] of .01). Analysis of additional markers from that region delineated a candidate region of <1 cM, between markers D17S1787 and D17S934. Interestingly, the only marker not showing recombination with the disease locus was an intragenic marker of the thyroid-hormone receptor alpha1 (THRA1) gene, which generated a LOD score of 12.84 at straight theta=.00. Since thyroid hormones are known to stimulate bone resorption, the THRA1 gene might be involved in the etiology and pathogenesis of van Buchem disease. Unraveling the underlying mechanism for this disorder could contribute to the understanding of the regulatory processes conditioning bone density and the underlying pathological processes.


Subject(s)
Chromosomes, Human, Pair 17 , Hyperostosis, Cortical, Congenital/genetics , Chromosome Mapping , Consanguinity , Family , Female , Genes, Recessive , Genetic Markers , Genotype , Haplotypes , Humans , Hyperostosis, Cortical, Congenital/pathology , Lod Score , Male , Microsatellite Repeats , Netherlands , Nuclear Family , Pedigree , Polymorphism, Genetic , Sclerosis/genetics , Sclerosis/pathology
20.
Am J Hum Genet ; 60(5): 1168-73, 1997 May.
Article in English | MEDLINE | ID: mdl-9150164

ABSTRACT

We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.


Subject(s)
Chromosomes, Human, Pair 11 , Genes, Dominant , Hearing Loss, Bilateral/genetics , Audiometry, Pure-Tone , Belgium , Chromosome Mapping , Female , Genetic Markers , Hearing Loss, Bilateral/diagnosis , Humans , Lod Score , Male , Pedigree
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