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1.
Biochim Biophys Acta ; 1841(3): 336-44, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24036494

ABSTRACT

Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata (CP) caused by mutations in one gene of the distal pathway of cholesterol biosynthesis. It exhibits intense phenotypic variation and primarily affects the skin, bones and eyes. The ichthyosis following Blaschko's lines, chondrodysplasia punctata and cataracts are the typical clinical findings. The cardinal biochemical features are an increase in 8(9)-cholestenol and 8-dehydrocholesterol (8DHC), which suggest a deficiency in 3ß-hydroxysteroid-Δ8,Δ7-isomerase, also called emopamil binding protein (EBP). The EBP gene is located on the short arm of the X chromosome (Xp11.22-p11.23) and encodes a 230 amino acid protein with dual function. Explaining the clinical phenotype in CDPX2 implies an understanding of both the genetics and biochemical features of this disease. CDPX2 displays an X-linked dominant pattern of inheritance, which is responsible for the distribution of lesions in some tissues. The clinical phenotype in CDPX2 results directly from impairment in cholesterol biosynthesis, and indirectly from abnormalities in the hedgehog signaling protein pathways. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.


Subject(s)
Cholesterol , Chondrodysplasia Punctata , Chromosomes, Human, X/genetics , Genes, Dominant , Mutation , Steroid Isomerases , Cholestadienols/metabolism , Cholesterol/biosynthesis , Cholesterol/genetics , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Chondrodysplasia Punctata/pathology , Female , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Infant , Infant, Newborn , Male , Signal Transduction/genetics , Steroid Isomerases/genetics , Steroid Isomerases/metabolism
2.
Am J Med Genet A ; 149A(11): 2464-8, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19839041

ABSTRACT

Brachytelephalangic chondrodysplasia punctata (CDPX1) is an X-linked recessive disorder caused by mutations in the arylsulfatase E (ARSE) gene, characterized by the presence of stippled epiphyses on radiograms in infancy and early childhood. Other features include hypoplasia of the midface and of the nasal bone, short stature, brachytelephalangy, and ectopic calcifications. Patients display marked clinical variability and there is no clear genotype-phenotype correlation. We report on a 14-month-old boy who presented with respiratory stridor due to tracheal calcifications. He had mild midface hypoplasia and brachytelephalangy, but lacked other features of CDPX1, such as short stature and epiphyseal stippling. Analysis of ARSE detected a deletion involving exons 7-10. His maternal grandfather harbored the same defect but lacked any clinical manifestation. These findings underscore two important points. First, the absence of stippled epiphyses on radiograms should not be considered an exclusion criteria for ARSE mutation screening in patients with other features of the disease, especially after the neonatal period. Second, counseling to parents of affected children should be cautious because although the theoretical risk of inheriting the ARSE mutation is 50% for every male child of a carrier mother, it is not possible to determine whether he will develop features of CDPX1 and the eventual severity of symptoms. The actual risk of developing the disease is probably lower than 50%. Conversely, normal prenatal sonography does not rule out potentially severe complications such as tracheal stenosis.


Subject(s)
Chondrodysplasia Punctata/genetics , Genetic Diseases, X-Linked/genetics , Quantitative Trait, Heritable , Adult , Arylsulfatases/genetics , Chondrodysplasia Punctata/enzymology , Chromosomes, Human, Y/genetics , Female , Genetic Diseases, X-Linked/enzymology , Humans , Infant , Infant, Newborn , Male , Pregnancy , Pseudogenes/genetics , Radiography, Thoracic , Tomography, X-Ray Computed
3.
Proc Natl Acad Sci U S A ; 105(33): 11605-12, 2008 Aug 19.
Article in English | MEDLINE | ID: mdl-18695242

ABSTRACT

Sulfation is an important biological process that modulates the function of numerous molecules. It is directly mediated by cytosolic and Golgi sulfotransferases, which use 3'-phosphoadenosine 5'-phosphosulfate to produce sulfated acceptors and 3'-phosphoadenosine 5'-phosphate (PAP). Here, we identify a Golgi-resident PAP 3'-phosphatase (gPAPP) and demonstrate that its activity is potently inhibited by lithium in vitro. The inactivation of gPAPP in mice led to neonatal lethality, lung abnormalities resembling atelectasis, and dwarfism characterized by aberrant cartilage morphology. The phenotypic similarities of gPAPP mutant mice to chondrodysplastic models harboring mutations within components of the sulfation pathway lead to the discovery of undersulfated chondroitin in the absence of functional enzyme. Additionally, we observed loss of gPAPP leads to perturbations in the levels of heparan sulfate species in lung tissue and whole embryos. Our data are consistent with a model that clearance of the nucleotide product of sulfotransferases within the Golgi plays an important role in glycosaminoglycan sulfation, provide a unique genetic basis for chondrodysplasia, and define a function for gPAPP in the formation of skeletal elements derived through endochondral ossification.


Subject(s)
Bone and Bones/embryology , Bone and Bones/enzymology , Enzyme Inhibitors/pharmacology , Golgi Apparatus/drug effects , Golgi Apparatus/enzymology , Lithium/pharmacology , Nucleotidases/antagonists & inhibitors , Sulfur/metabolism , Animals , Animals, Newborn , Body Patterning , Cartilage/embryology , Cartilage/enzymology , Cells, Cultured , Chondrodysplasia Punctata/embryology , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Chondroitin/metabolism , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/enzymology , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Growth Plate/abnormalities , Growth Plate/enzymology , Heparitin Sulfate/metabolism , Male , Mice , Mice, Transgenic , Nucleotidases/genetics , Nucleotidases/metabolism , Phylogeny
4.
Am J Med Genet A ; 146A(8): 997-1008, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18348268

ABSTRACT

X-linked Recessive Chondrodysplasia Punctata (CDPX1) is due to a defect in arylsulfatase E (ARSE), located on Xp22.3. Neither the substrate nor function of the encoded warfarin-sensitive arylsulfatase has been identified and molecular analysis remains the only confirmatory diagnostic test. Nevertheless, the majority of patients evaluated have not had identifiable mutations in ARSE, and thus far 23 patients have been reported. The major clinical features in these patients are also present in a group now recognized as phenocopies, due to vitamin K deficiency in early gestation or maternal autoimmune disease. We evaluated the ARSE gene in 11 patients who met clinical criteria for CDPX1. We amplified all exons and intronic flanking sequence from each patient, and investigated suspected deletions or rearrangements by southern analysis. We identified mutations in seven individuals. Of the remainder, three had maternal conditions that further expand the phenocopy group. Thus, this group might represent a proportion of the mutation-negative patients in previous studies. We extracted clinical information from all prior reports over the past decade and show that there are few distinguishing features on examination between these two groups of patients. This study supports heterogeneity for CDPX1-like phenotypes and sorting these out will help to define the biological pathway and genetic contributors.


Subject(s)
Arylsulfatases/genetics , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/pathology , DNA Mutational Analysis , Genetic Diseases, X-Linked/enzymology , Genetic Diseases, X-Linked/pathology , Airway Obstruction/pathology , Cervical Vertebrae/abnormalities , Child , Child, Preschool , Chondrodysplasia Punctata/genetics , Chromosomes, Human, X/genetics , Genetic Diseases, X-Linked/genetics , Humans , Infant , Male , Vitamin K Deficiency/pathology
5.
Eur J Med Genet ; 50(5): 392-8, 2007.
Article in English | MEDLINE | ID: mdl-17625999

ABSTRACT

X-linked dominant chondrodysplasia punctata (Conradi-Hünermann disease, CDPX2) is characterised by short stature, stippled epiphyses, cataracts, ichthyosiform erythroderma and patchy alopecia of the scalp. The disorder is caused by mutations within the emopamil binding protein (EBP) gene encoding a 3beta-hydroxysteroid-Delta(8),Delta(7)-isomerase. The intrafamilial variation of disease severity is a known feature of CDPX2 probably caused by skewed X-inactivation. We report on a female fetus with typical symptoms of CDPX2 such as short limbs, postaxial polydactyly, ichthyotic skin lesions and punctate calcifications. Molecular genetic analysis of the EBP gene revealed a nonsense mutation (c.328C>T, p.R110X), which was previously detected in one CDPX2 patient and in a second female patient, who was only affected on one body side and erroneously diagnosed as CHILD syndrome. Surprisingly, the mother of our fetus carries the same mutation without having any signs of CDPX2. X-inactivation studies did not reveal any evidence of skewing neither in the mother nor in the fetus.


Subject(s)
Chondrodysplasia Punctata/genetics , Genetic Diseases, X-Linked/genetics , Adult , Chondrodysplasia Punctata/enzymology , Chromosomes, Human, X/genetics , Codon, Nonsense , Female , Genes, Dominant , Genetic Diseases, X-Linked/enzymology , Humans , Penetrance , Phenotype , Pregnancy , Prenatal Diagnosis , Steroid Isomerases/genetics , X Chromosome Inactivation
6.
Prenat Diagn ; 26(13): 1235-40, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17086568

ABSTRACT

OBJECTIVE: To report our experience of the prenatal diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) and highlight its variable phenotypic presentation. METHODS: We report the sonographic features of three female fetuses affected with CDPX2. The ultrasound, radiographic and pathological findings were compared. RESULTS: Family 1: Two affected pregnancies, both terminated. Fetus 1: Presented with epiphyseal stippling involving the vertebrae, upper and lower limbs, asymmetric shortening of the long bones and flat facial profile. Fetus 2: Prenatal findings included premature epiphyseal stippling, paravertebral cartilaginous calcific foci, mild shortening of the long bones and flat facies. Mutation analysis of the mother and both fetuses revealed mutation in the emopamil-binding protein (EBP) gene. Family 2: Prenatal sonography showed scattered epiphyseal stippling, minimal vertebral segmentation anomalies, mild asymmetric limb shortening and flat facies. Female infant delivered at 39 weeks of gestation. Biochemical analysis in all three fetuses showed increased levels of serum 8(9)-cholestenol consistent with delta (8), delta (7)-isomerase deficiency and CDPX2. CONCLUSION: Prenatal diagnosis of CDPX2 is difficult because of marked phenotypic variation. Epiphyseal stippling, ectopic paravertebral calcifications, asymmetric shortening of long bones and dysmorphic flattened facies are crucial for prenatal diagnosis. DNA analysis of the CDPX2 gene and biochemical determination of the serum 8(9)-cholestenol level are important for diagnosis, especially if future pregnancies are planned.


Subject(s)
Chondrodysplasia Punctata/diagnostic imaging , Chondrodysplasia Punctata/genetics , Chromosomes, Human, X , Genes, Dominant/genetics , Ultrasonography, Prenatal , Abnormalities, Multiple , Adult , Autopsy , Cholesterol/blood , Chondrodysplasia Punctata/enzymology , DNA Mutational Analysis , Family Health , Fatal Outcome , Female , Gestational Age , Humans , Phenotype , Pregnancy , Steroid Isomerases/deficiency , Steroid Isomerases/genetics
7.
Gene ; 336(2): 155-61, 2004 Jul 21.
Article in English | MEDLINE | ID: mdl-15246527

ABSTRACT

Despite many efforts, the mouse homolog of ARSE, the gene implicated in X-linked recessive chondrodysplasia punctata, has not yet been identified. This absence has so far impaired a deep study of the role of this gene. For this reason, we searched the avian homolog and here report the identification of a chicken sulfatase, cARS, that shares high degree of homology with the cluster of sulfatases located on the short arm of the human X chromosome. cARS activity against a sulfated artificial substrate is heat labile and inhibited by warfarin, features that are characteristic of ARSE. The expression in pharyngeal arches, somites, and leg buds during chick development is consistent with cARS being the functional ortholog of ARSE, matching the tissues affected in this genetic disorder. The identification of the ARSE chicken gene is an important step for the study of its natural substrate and its role during development.


Subject(s)
Arylsulfatases/genetics , Chickens/genetics , Amino Acid Sequence , Animals , Arylsulfatases/metabolism , COS Cells , Chick Embryo , Chlorocebus aethiops , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Electrophoresis, Polyacrylamide Gel , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Genetic Diseases, X-Linked/enzymology , Genetic Diseases, X-Linked/genetics , Humans , Immunoblotting , In Situ Hybridization , Molecular Sequence Data , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Analysis, DNA , Sequence Homology, Amino Acid
8.
Am J Med Genet A ; 117A(2): 164-8, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12567415

ABSTRACT

X-linked chondrodysplasia punctata (CDPX1), due to mutations of the arylsulfatase E (ARSE) gene, is a congenital disorder characterized by abnormalities in cartilage and bone development. We performed mutational analysis of the ARSE gene in a series of 16 male patients, and we found mutations in 12 subjects. Clinical variability was observed among the patients, including severe presentations with early lethality in one of them, and symptoms such as cataract and respiratory distress. This indicates that the clinical spectrum of CDPX1, commonly considered a relatively mild form of chondrodysplasia punctata, is wider than previously reported. Different types of mutations were found among the patients examined. Three missense mutations (I80N, T481M, P578S) were expressed in Cos7 cells to study the effects on arylsulfatase E catalytic activity. These mutations caused impaired enzymatic activity suggesting that they are responsible for the disease. Two nonsense mutations, W581X in four patients and R540X in one, were found. One patient showed an insertion (T616ins). In three patients we found deletions of the ARSE gene: in one the deletion involved only the 3' end of the gene, while in two the ARSE gene was completely deleted.


Subject(s)
Arylsulfatases/genetics , Chondrodysplasia Punctata/genetics , X Chromosome/genetics , Amino Acid Substitution , Animals , Arylsulfatases/metabolism , COS Cells , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/pathology , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Genes, Recessive/genetics , Genetic Linkage , Humans , Male , Mutation , Point Mutation
9.
Neuropediatrics ; 32(3): 113-22, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11521206

ABSTRACT

Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only been recently described and more are likely to follow in the near future. Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. The other recognized defects of cholesterol biosynthesis are due to enzyme defects located distally in the pathway beyond the branching points of nonsterol isoprene biosynthesis and solely affecting cholesterol biosynthesis. Patients with these disorders all present with complex malformation syndromes involving different organ systems. The main characteristics of CHILD syndrome and Conradi-Huenermann syndrome are skeletal defects and ichthyosiform skin involvement. Smith-Lemli-Opitz syndrome and desmosterolosis are generalized malformation syndromes involving many different organs including the central nervous system.The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity, whereas the search for the distally located defects of cholesterol biosynthesis requires sterol analysis in blood or tissues by GCMS. Rational therapeutic approaches have been described for HIDS, MVA and Smith-Lemli-Opitz syndrome.


Subject(s)
Cholesterol/biosynthesis , Lipid Metabolism, Inborn Errors/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/enzymology , Abnormalities, Multiple/genetics , Alleles , Child , Chondrodysplasia Punctata/diagnosis , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Humans , Hypergammaglobulinemia/diagnosis , Hypergammaglobulinemia/enzymology , Hypergammaglobulinemia/genetics , Immunoglobulin D/blood , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/enzymology , Mevalonic Acid/urine , Phosphotransferases (Alcohol Group Acceptor)/genetics , Smith-Lemli-Opitz Syndrome/diagnosis , Smith-Lemli-Opitz Syndrome/enzymology , Smith-Lemli-Opitz Syndrome/genetics
10.
Eur J Dermatol ; 10(6): 425-8, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10980461

ABSTRACT

We here review the clinical and genetic features of the Conradi-Hünermann-Happle syndrome. The disease is characterized by chondrodysplasia punctata, linear ichthyosis, cataract, and short stature. The X-linked dominant mode of inheritance was first recognized by Rudolf Happle in the years 1977 to 1981, who also fully delineated the clinical spectrum of this clinico-genetic entity. In the past, linkage studies had firmly excluded the gene for this syndrome from the Xq28 region, but unfortunately had also failed to clearly map the gene elsewhere on the X-chromosome. Very recently, causative mutations were identified in a large number of patients in the gene for emopamil binding protein. This gene is located on the short arm of Xp11.22-23 and also acts as a D8-D7 sterol isomerase. This enzymatic function plays a crucial role in cholesterol biosynthesis. It is of note that very recent investigations by the Marburg group have disclosed that the CHILD syndrome is likewise caused by a similar metabolic defect, namely a deficiency of a 3b-hydroxysteroid dehydrogenase (NSDHL). In the pathway of cholesterol biosynthesis this enzyme functions "upstream" of D8-D7 sterol isomerase and was shown to underlie the mouse mutant bare patches. Molecular studies in these syndromes now allow us to determine which family members carry the mutation and have already provided evidence in the Conradi-Hünermann-Happle syndrome for both gonadal and somatic mosaicism. As gonadal mosaicism seems to be frequent in this disease, a recurrence risk for further pregnancies has to be considered when dealing with a seemingly sporadic case.


Subject(s)
Chondrodysplasia Punctata/enzymology , Skin Diseases, Genetic/enzymology , Steroid Isomerases/genetics , 3-Hydroxysteroid Dehydrogenases/deficiency , Chondrodysplasia Punctata/genetics , Chondrodysplasia Punctata/pathology , Humans , Mutation , Skin Diseases, Genetic/pathology , Syndrome
11.
Nat Genet ; 22(3): 286-90, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10391218

ABSTRACT

Tattered (Td) is an X-linked, semi-dominant mouse mutation associated with prenatal male lethality. Heterozygous females are small and at 4-5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults. Craniofacial anomalies and twisted toes have also been observed in some affected females. A potential second allele of Td has also been described. The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata (CDPX2, alternatively known as X-linked dominant Conradi-Hünermann-Happle syndrome) as well as another X-linked, semi-dominant mouse mutation, bare patches (Bpa). The Bpa gene has recently been identified and encodes a protein with homology to 3beta-hydroxysteroid dehydrogenases that functions in one of the later steps of cholesterol biosynthesis. CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling and craniofacial defects (MIM 302960). We have now identified the defect in Td mice as a single amino acid substitution in the delta8-delta7 sterol isomerase emopamil binding protein (Ebp; encoded by Ebp in mouse) and identified alterations in human EBP in seven unrelated CDPX2 patients.


Subject(s)
Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Mutation , Steroid Isomerases/genetics , X Chromosome/genetics , Amino Acid Sequence , Animals , Base Sequence , Carrier Proteins/chemistry , Carrier Proteins/genetics , DNA Primers/genetics , Female , Genes, Dominant , Genetic Linkage , Guinea Pigs , Humans , Male , Mice , Mice, Mutant Strains , Molecular Sequence Data , Phenotype , Pregnancy , Sequence Homology, Amino Acid , Steroid Isomerases/chemistry
12.
Nat Genet ; 22(3): 291-4, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10391219

ABSTRACT

X-linked dominant Conradi-Hünermann syndrome (CDPX2; MIM 302960) is one of a group of disorders with aberrant punctate calcification in cartilage, or chondrodysplasia punctata (CDP). This is most prominent around the vertebral column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis and atrophoderma. The phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. CDPX2 is presumed lethal in males, although a few affected males have been reported. We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples from seven female probands with CDPX2 (ref. 4). This pattern of accumulated cholesterol intermediates suggested a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-delta8-isomerase (EBP) has been identified and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands. We confirmed the functional significance of two missense alleles by expressing them in a sterol-delta8-isomerase-deficient yeast strain. Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and suggest a role for sterols in bone development.


Subject(s)
Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Mutation , Steroid Isomerases/genetics , X Chromosome/genetics , Adolescent , Base Sequence , Carrier Proteins/genetics , Child , DNA/genetics , DNA Primers/genetics , Female , Genetic Linkage , Humans , Infant, Newborn , Molecular Sequence Data , Pregnancy
14.
J Med Genet ; 35(12): 1004-8, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9863597

ABSTRACT

Sixteen males and two females with symmetrical (mild) type of chondrodysplasia punctata were tested for mutations in the X chromosome located arylsulphatase D and E genes. We identified one nonsense and two missense mutations in the arylsulphatase E gene in three males. No mutations were detected in the arylsulphatase D gene. Family studies showed segregation of the mutant genes establishing X linked inheritance for these families. Asymptomatic females and males were found in these studies. The clinical presentation varies not only between unrelated affected males, but also between affected males within the same family. We also conclude that clinical diagnosis of chondrodysplasia punctata in adults can be difficult. Finally, our results indicate that brachytelephalangy is not necessarily a feature of X linked symmetrical chondrodysplasia punctata.


Subject(s)
Arylsulfatases/genetics , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , Mutation , Amino Acid Sequence , Child, Preschool , Chondrodysplasia Punctata/physiopathology , Female , Humans , Infant , Male , Molecular Sequence Data , Pedigree , Polymorphism, Genetic
15.
Am J Hum Genet ; 62(3): 562-72, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9497243

ABSTRACT

X-linked chondrodysplasia punctata (CDPX) is a congenital disorder characterized by abnormalities in cartilage and bone development. Mutations leading to amino acid substitutions were identified recently in CDPX patients, in the coding region of the arylsulfatase E (ARSE) gene, a novel member of the sulfatase gene family. Transfection of the ARSE full-length cDNA, in Cos7 cells, allowed us to establish that its protein product is a 60-kD precursor, which is subject to N-glycosylation, to give a mature 68-kD form that, unique among sulfatases, is localized to the Golgi apparatus. Five missense mutations found in CDPX patients were introduced into wild-type ARSE cDNA by site-directed mutagenesis. These mutants were transfected into Cos7 cells, and the arylsulfatase activity and biochemical properties were determined, to study the effect of these substitutions on the ARSE protein. One of the mutants behaves as the wild-type protein. All four of the other mutations resulted in a complete lack of arylsulfatase activity, although the substitutions do not appear to affect the stability and subcellular localization of the protein. The loss of activity due to these mutations confirms their involvement in the clinical phenotype and points to the importance of these residues in the correct folding of a catalytically active ARSE enzyme.


Subject(s)
Arylsulfatases/genetics , Chondrodysplasia Punctata/genetics , Genetic Linkage , Mutation , X Chromosome , Animals , COS Cells , Chondrodysplasia Punctata/enzymology , Humans , Mutagenesis, Site-Directed , Subcellular Fractions/enzymology , Transfection
16.
J Inherit Metab Dis ; 20(6): 807-10, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9427150

ABSTRACT

Ten of 31 patients with steroid sulphatase (STS) deficiency were found to have an allergic disease (bronchial asthma, allergic rhinitis, or atopic dermatitis). STS deficiency may predispose patients to allergic disease.


Subject(s)
Arylsulfatases/deficiency , Hypersensitivity/enzymology , Adolescent , Adult , Arylsulfatases/genetics , Asthma/enzymology , Child , Child, Preschool , Chondrodysplasia Punctata/enzymology , Dermatitis, Atopic/enzymology , Gene Deletion , Humans , Ichthyosis/enzymology , Immunoglobulin E/blood , Kallmann Syndrome/enzymology , Rhinitis, Allergic, Perennial/enzymology , Steryl-Sulfatase
17.
Dermatology ; 192(1): 23-7, 1996.
Article in English | MEDLINE | ID: mdl-8832947

ABSTRACT

BACKGROUND: We examined an 18-month-old girl with typical clinical features of X-linked dominant chondrodysplasia punctata (CDPX2) with decreased activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT), previously reported in CDPX2. On the other hand, steroid sulfatase, whose activity is deficient or decreased in X-linked ichthyosis and X-linked recessive chondrodysplasia punctata, has been reported to be normal in CDPX2, although all of these diseases have ichthyotic skin changes. OBJECTIVE: We measured the activity of DHAP-AT and steroid sulfatase of the patients fibroblasts to confirm the DHAP-AT abnormality in CDPX2. RESULTS: The DHAP-AT activity was remarkably reduced, but steroid sulfatase activity was within normal levels when compared with those of 2 healthy controls. CONCLUSION: The abnormal metabolism in plasmalogen synthesis in CDPX2 was confirmed. It is, however, unknown how the decreased DHAP-AT activity is related to the skin changes.


Subject(s)
Acyltransferases/metabolism , Chondrodysplasia Punctata/enzymology , Chondrodysplasia Punctata/genetics , X Chromosome/pathology , Acyltransferases/analysis , Cells, Cultured , Chondrodysplasia Punctata/diagnosis , Chondrodysplasia Punctata/physiopathology , Female , Fibroblasts/metabolism , Genetic Linkage , Humans , Infant, Newborn
18.
Cell ; 81(1): 15-25, 1995 Apr 07.
Article in English | MEDLINE | ID: mdl-7720070

ABSTRACT

X-linked recessive chondrodysplasia punctata (CDPX) is a congenital defect of bone and cartilage development characterized by aberrant bone mineralization, severe underdevelopment of nasal cartilage, and distal phalangeal hypoplasia. A virtually identical phenotype is observed in the warfarin embryopathy, which is due to the teratogenic effects of coumarin derivatives during pregnancy. We have cloned the genomic region within Xp22.3 where the CDPX gene has been assigned and isolated three adjacent genes showing highly significant homology to the sulfatase gene family. Point mutations in one of these genes were identified in five patients with CDPX. Expression of this gene in COS cells resulted in a heat-labile arylsulfatase activity that is inhibited by warfarin. A deficiency of a heat-labile arylsulfatase activity was demonstrated in patients with deletions spanning the CDPX region. These data indicate that CDPX is caused by an inherited deficiency of a novel sulfatase and suggest that warfarin embryopathy might involve drug-induced inhibition of the same enzyme.


Subject(s)
Abnormalities, Drug-Induced/etiology , Arylsulfatases/genetics , Chondrodysplasia Punctata/genetics , Multigene Family/genetics , Point Mutation/genetics , Warfarin/pharmacology , X Chromosome , Amino Acid Sequence , Base Sequence , Cell Line , Chondrodysplasia Punctata/enzymology , Chromosome Mapping , Cloning, Molecular , Fibroblasts/enzymology , Gene Expression Regulation, Enzymologic , Humans , Male , Molecular Sequence Data , Organ Specificity , RNA, Messenger/analysis , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Warfarin/adverse effects
20.
Ultrastruct Pathol ; 17(6): 623-36, 1993.
Article in English | MEDLINE | ID: mdl-8122328

ABSTRACT

In the liver biopsy from an 8.5-year-old girl with the biochemical characteristics of rhizomelic chondrodysplasia punctata (RCDP), but with normal limbs, normal catalase-containing peroxisomes were absent. Light microscopy after diaminobenzidine staining for catalase activity (the peroxisomal marker enzyme) and immunostaining against catalase protein indicated a cytosolic localization of the enzyme. By electron microscopy, rare and extremely large, irregularly shaped vesicles were found in the parenchymal cells. The three peroxisomal beta-oxidation enzymes (acyl-CoA oxidase, bi(tri)functional enzyme, and 3-ketoacyl-CoA thiolase) and alanine-glyoxylate aminotransferase were immunolocalized in these organelles. However, a weak to negative label was obtained after staining against catalase. Diaminobenzidine staining demonstrated a minimal catalase reaction product in some vesicles only. Morphometry revealed a corrected mean d-circle of 1.44 microns and a maximum d-circle of 2.767 microns (controls: 0.635 microns and 1.027 microns, respectively). Numerical, volume, and surface densities were reduced to 3%, 41%, and 17% of control values, respectively. The large size, irregular shape, and rarity of the organelles are morphologic features of peroxisomal "ghosts." It seems that in this patient, apart from the known peroxisomal defects in RCDP, catalase incorporation into the peroxisomes is impaired together with a normal proliferation (division) of the organelles. In the cultured skin fibroblasts from the patient, however, immuno-electron microscopy showed normal catalase-containing peroxisomes in apparently normal numbers.


Subject(s)
Catalase/metabolism , Chondrodysplasia Punctata/pathology , Cytoplasm/enzymology , Liver/ultrastructure , Microbodies/ultrastructure , Child , Chondrodysplasia Punctata/enzymology , Female , Fibroblasts/enzymology , Histocytochemistry , Humans , Liver/enzymology , Microscopy, Electron , Microscopy, Immunoelectron
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