RESUMO
Unbalanced translocations involving X and Y chromosomes are rare and associated with a contiguous gene syndrome. The clinical phenotype is heterogeneous including mainly short stature, chondrodysplasia punctata, ichthyosis, hypogonadism, and intellectual disability. Here, we report 2 brothers with peculiar gestalt, short stature, and hearing loss, who harbor an X/Y translocation. Physical examination, brainstem acoustic potential evaluation, bone age, hormonal assessment, and X-ray investigations were performed. Because of their dysmorphic features, karyotyping, FISH, and aCGH were carried out. The probands had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, normal intelligence as well as slight radial and ulnar bowing with brachytelephalangy. R-banding identified a derivative X chromosome with an abnormally expanded short arm. The mother was detected as a carrier of the same aberrant X chromosome. aCGH disclosed a 3.1-Mb distal deletion of chromosome region Xp22.33pter. This interval encompasses several genes, especially the short stature homeobox (SHOX) and arylsulfatase (ARSE) genes. The final karyotype of the probands was: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(DXYS129-,DXYS153-)mat.arr[hg19] Xp22.33(61091_2689408)×1mat,Xp22.33(2701273_3258404)×0mat,Yq11.222q12 (21412851_59310245)×2. Herein, we describe a Moroccan family with a maternally inherited X/Y translocation and discuss the genotype-phenotype correlations according to the deleted genes.
Assuntos
Anormalidades Múltiplas/genética , Arilsulfatases/genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Perda Auditiva Bilateral/genética , Perda Auditiva Neurossensorial/genética , Translocação Genética , Arilsulfatases/deficiência , Cromossomos Humanos X/ultraestrutura , Cromossomos Humanos Y/ultraestrutura , Consanguinidade , Feminino , Humanos , Hipertelorismo/genética , Recém-Nascido , Cariotipagem , Masculino , Pessoa de Meia-Idade , Marrocos , Linhagem , Fenótipo , Rádio (Anatomia)/anormalidades , Escoliose/genética , Irmãos , Ulna/anormalidades , Adulto JovemRESUMO
PURPOSE: Retinal degeneration is a common feature of several lysosomal storage disorders, including the mucopolysaccharidoses, a group of metabolic disorders that is characterized by widespread accumulation of glycosaminoglycans due to lysosomal enzyme dysfunction. We used a new mouse model of mucopolysaccharidosis IIIE to study the effect of Arylsulfatase G (ARSG) deficiency on retina integrity. METHODS: The retina of Arsg knockout mice aged 1 to 24 months was studied by immunohistochemistry and Western blot analysis. Electron microscopic analyses were performed on retinas from 15- and 22-month-old animals. Photoreceptor and microglia cell numbers and retina thickness were determined to quantitatively characterize retinal degeneration in ARSG-deficient mice. RESULTS: Arsg knockout mice showed a progressive degeneration of photoreceptor cells starting between 1 and 6 months of age, resulting in the loss of more than 50% of photoreceptor cells in 24-month-old mice. Photoreceptor loss was accompanied by reactive astrogliosis, reactive microgliosis that was evident in the outer but not inner retina, and elevated expression levels of some lysosomal proteins. Electron microscopic analyses of retinas revealed no evidence for the presence of storage vacuoles. Of note, expression of ARSG protein in wild-type mice was detectable only in the RPE which, however, appeared morphologically unaffected in knockout mice at the electron microscopic level. CONCLUSIONS: To our knowledge, this is the first study demonstrating that ARSG deficiency results in progressive photoreceptor degeneration and dysregulation of various lysosomal proteins.
Assuntos
Arilsulfatases/deficiência , Modelos Animais de Doenças , Mucopolissacaridose III/enzimologia , Células Fotorreceptoras/enzimologia , Degeneração Retiniana/enzimologia , Animais , Arilsulfatases/metabolismo , Western Blotting , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Mucopolissacaridose III/diagnóstico , Células Fotorreceptoras/patologia , Proteínas/metabolismo , Degeneração Retiniana/diagnóstico , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
Deficiency of arylsulfatase G (ARSG) leads to a lysosomal storage disease in mice resembling biochemical and pathological features of the mucopolysaccharidoses and particularly features of mucopolysaccharidosis type III (Sanfilippo syndrome). Here we show that Arsg KO mice share common neuropathological findings with other Sanfilippo syndrome models and patients, but they can be clearly distinguished by the limitation of most phenotypic alterations to the cerebellum, presenting with ataxia as the major neurological finding. We determined in detail the expression of ARSG in the central nervous system and observed highest expression in perivascular macrophages (which are characterized by abundant vacuolization in Arsg KO mice) and oligodendrocytes. To gain insight into possible mechanisms leading to ataxia, the pathology in older adult mice (>12 months) was investigated in detail. This study revealed massive loss of Purkinje cells and gliosis in the cerebellum, and secondary accumulation of glycolipids like GM2 and GM3 gangliosides and unesterified cholesterol in surviving Purkinje cells, as well as neurons of some other brain regions. The abundant presence of ubiquitin and p62-positive aggregates in degenerating Purkinje cells coupled with the absence of significant defects in macroautophagy is consistent with lysosomal membrane permeabilization playing a role in the pathogenesis of Arsg-deficient mice and presumably Sanfilippo disease in general. Our data delineating the phenotype of mucopolysaccharidosis IIIE in a mouse KO model should help in the identification of possible human cases of this disease.
Assuntos
Arilsulfatases/deficiência , Ataxia/enzimologia , Mucopolissacaridose III/enzimologia , Animais , Arilsulfatases/genética , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Cerebelo/citologia , Cerebelo/metabolismo , Modelos Animais de Doenças , Feminino , Gliose/metabolismo , Glicolipídeos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Mucopolissacaridose III/genética , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/patologia , Células de Purkinje/metabolismoRESUMO
AIM: Motor deterioration is a key feature in metachromatic leukodystrophy (MLD). The lack of data about its natural course impedes evaluation of therapeutic interventions. This study aimed to provide data about motor decline in MLD. METHOD: Fifty-nine patients (27 males, 32 females) with MLD (21 with late-infantile MLD and 38 with juvenile MLD) were recruited within a nationwide survey (the German LEUKONET). Median (range) age at onset was 17 months (9-27) for the group with late-infantile MLD and 6 years 2 months (2y 11mo-14y) for the group with juvenile MLD. Gross motor function was assessed using the Gross Motor Function Classification for MLD. RESULTS: In late-infantile MLD, all patients showed loss of all gross motor function until 3 years 4 months of age. Patients with juvenile MLD showed a more variable and significantly longer motor decline (p<0.001). For a patient with the juvenile form showing first gait disturbances, the probability of remaining stable for more than 1 year was 84%, and 51% for more than 2 years. Having lost independent walking, subsequent motor decline was as steep as in the late-infantile form (median 5 mo, interquartile range 3-22). INTERPRETATION: The course of motor disease was more variable in juvenile MLD with respect to onset and dynamics. However, the motor decline after the loss of independent walking was similarly steep in both forms. These data can serve as a reference for clinical studies that are topics of current research and allow definition of inclusion/exclusion criteria.
Assuntos
Leucodistrofia Metacromática/complicações , Transtornos dos Movimentos/etiologia , Adolescente , Idade de Início , Arilsulfatases/deficiência , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/métodos , Feminino , Inquéritos Epidemiológicos , Humanos , Estimativa de Kaplan-Meier , Leucodistrofia Metacromática/tratamento farmacológico , Leucodistrofia Metacromática/epidemiologia , Leucodistrofia Metacromática/mortalidade , Masculino , Transtornos dos Movimentos/epidemiologia , Transtornos dos Movimentos/mortalidade , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.
Assuntos
Arilsulfatases/genética , Doenças do Cão/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/veterinária , Transportadores de Cassetes de Ligação de ATP/genética , Fatores Etários , Animais , Arilsulfatases/deficiência , Domínio Catalítico/genética , Linhagem Celular , Córtex Cerebelar/metabolismo , Córtex Cerebelar/patologia , Córtex Cerebelar/ultraestrutura , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Doenças do Cão/enzimologia , Cães , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Lysosomal exocytosis is a ubiquitously occurring process, which has a physiological role in repair of wounds of the plasma membrane. Lysosomal storage disorders are a group of more than 40 different diseases, which are characterized by intralysosomal storage of various substances. Metachromatic leukodystrophy is a lysosomal disease caused by the deficiency of arylsulfatase A, which results in the storage of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide) in, e.g., oligodendrocytes and distal tubule kidney cells. Here we show that sulfatide storing cultured primary kidney cells of arylsulfatase A deficient mice can undergo calcium induced lysosomal exocytosis and that this results in the delivery of storage material to the culture medium. In metachromatic leukodystrophy extracellular sulfatide has been found in urine and cerebrospinal fluid. Lysosomal exocytosis may explain the presence of sulfatide in these body fluids.
Assuntos
Exocitose/fisiologia , Doenças por Armazenamento dos Lisossomos/metabolismo , Lisossomos/metabolismo , Animais , Arilsulfatases/deficiência , Arilsulfatases/metabolismo , Arilsulfatases/farmacologia , Cálcio/metabolismo , Células Cultivadas , Galactosilceramidas/química , Galactosilceramidas/metabolismo , Túbulos Renais Distais/metabolismo , Leucodistrofia Metacromática/metabolismo , Camundongos , Camundongos Knockout , Camundongos Mutantes , Oligodendroglia/metabolismo , Sulfoglicoesfingolipídeos/metabolismoRESUMO
Mucopolysaccharidoses are a type of lysosomal storage disorders characterized by defect in the degradation of Mucopolysaccharides due to deficiency of specific lysosomal enzymes leading to their accumulation in various tissues. MPS -VI (Maroteaux-Lamy Syndrome) is an autosomal recessive syndrome due to deficiency of enzyme Aryl- Sulfatase -B, and is characterized by characteristic facies, normal intelligence, Dysostosis multiplex, organomegaly, joint stiffness, corneal clouding and striking inclusions in peripheral blood leucocytes. We present an 8-year-old male child with MPS-VI syndrome, confirmed by enzyme assay.
Assuntos
Mucopolissacaridose VI/diagnóstico , Anormalidades Múltiplas , Arilsulfatases/deficiência , Criança , Nanismo , Humanos , Leucócitos/ultraestrutura , MasculinoRESUMO
Metachromatic leukodystrophy (MLD)--lysosomal storage disease caused arylsulfatase A (ARSA) deficiency. Biochemical diagnostic of MLD is complicated by arylsulfatase A pseudodeficiency. There is possibility of mistake in MLD diagnoses in case of pseudodeficiency ARSA and non-MLD neurological disease combination. We suggest the new modification of arylsulfatase A activity detection method which allows to identify the arylsulfatase A pseudodeficiency without molecular genetic methods.
Assuntos
Arilsulfatases/deficiência , Leucodistrofia Metacromática/diagnóstico , Adolescente , Adulto , Arilsulfatases/sangue , Arilsulfatases/genética , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Haplótipos , Humanos , Lactente , Leucócitos/enzimologia , Leucodistrofia Metacromática/sangue , Leucodistrofia Metacromática/genética , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: Metachromatic leukodystrophy is a lysosomal lipid storage disorder. It is caused by mutations in the gene for arylsulphatase A, an enzyme involved in the degradation of the sphingolipid 3'-O-sulphogalactosylceramide (sulphatide). This membrane lipid can be found in various cell types, but in particularly high concentrations in the myelin of the nervous system. Patients suffer from progressive, finally lethal, demyelination due to accumulation of sulphatide. In the nervous system, lipid storage not only affects oligodendrocytes but also neurons and, in addition, leads to astrogliosis and activation of microglia. At the cellular level, lysosomal sulphatide storage also affects the lipid composition of myelin itself and has consequences for the amount and localization of particular myelin membrane-associated proteins. Here we review data, largely based on an arylsulphatase A knock-out mouse model of metachromatic leukodystrophy. CONCLUSION: The knock-out mouse model of metachromatic leukodystrophy has provided insights into the histopathological and cellular consequences of sulphatide storage.
Assuntos
Leucodistrofia Metacromática/metabolismo , Animais , Arilsulfatases/deficiência , Arilsulfatases/genética , Membrana Celular/metabolismo , Cerebrosídeo Sulfatase , Modelos Animais de Doenças , Imuno-Histoquímica , Leucodistrofia Metacromática/enzimologia , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Knockout , Glicoproteína Associada a Mielina/metabolismoRESUMO
It has been previously reported that a low or absent maternal serum unconjugated estriol (uE3) level is associated with placental steroid sulfatase (STS) deficiency. Here we report a correlation between patients who present with a very low or absent maternal serum uE3 and a deletion of the STS gene as assessed by fluorescence in situ hybridization (FISH). We studied nine prenatal cases that presented to the clinical laboratory with an abnormal triple screen, specifically low or absent maternal serum uE3 and a 46,XY karyotype. FISH analysis showed complete deletion of a probe containing the STS gene in six cases and one case had a partial deletion (reduced but not absent signal). The remaining two cases were not deleted for the STS probe. All mothers tested whose fetus showed a deletion were shown to be STS deletion carriers using FISH. Biochemical analysis was performed on 7/9 prenatal specimens. All fetuses deleted for the STS probe were also found to be deficient for STS by biochemical analysis of cultured amniotic fluid (5/5). Of the two fetuses not deleted for the STS probe, one was deficient for STS activity, while the other had a normal result. The abnormal result of enzyme deficiency by biochemical analysis in a non-deletion case likely represents a mutation in the STS gene, not detectable by this FISH assay. Postnatal FISH confirmation of the STS deletion was performed in 1/7 cases. Clinical follow-up was available for 4/9 cases following birth.
Assuntos
Líquido Amniótico/enzimologia , Arilsulfatases/deficiência , Estriol/sangue , Hibridização in Situ Fluorescente , Gravidez/sangue , Diagnóstico Pré-Natal/métodos , Adulto , Líquido Amniótico/citologia , Arilsulfatases/genética , Biomarcadores/sangue , Cromossomos Humanos X , Feminino , Seguimentos , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Recém-Nascido , Masculino , Cariotipagem Espectral , Esteril-SulfataseRESUMO
Steroid sulfatase deficiency results in X-linked ichthyosis, an inborn error of metabolism in which the principal molecular defect is the complete deletion of the steroid sulfatase gene and flanking markers. Mosaicism for the steroid sulfatase gene has not yet been reported in X-linked ichthyosis. In this study we describe an X-linked ichthyosis patient with complete deletion of the steroid sulfatase gene and his mother with somatic and germinal mosaicism for this molecular defect. The family (X-linked ichthyosis patient, grandmother, mother, and sister) was analyzed through steroid sulfatase enzyme assay, polymerase chain reaction, DNA markers, and fluorescence in situ hybridization of the steroid sulfatase gene. Steroid sulfatase activity was undetectable in the X-linked ichthyosis patient, very low in the mother, and normal in the grandmother and sister. The X-linked ichthyosis patient showed a 2 Mb deletion of the steroid sulfatase gene and flanking regions from 5'DXS1139 to 3'DXF22S1. The mother showed one copy of the steroid sulfatase gene in 98.5% of oral cells and in 80% of leukocytes. The grandmother and sister showed two copies of the steroid sulfatase gene. The origin of the X chromosome with the deletion of the steroid sulfatase gene corresponded to the grandfather of the proband. We report the first case of somatic and germinal mosaicism of the steroid sulfatase gene in an X-linked ichthyosis carrier and propose DNA slippage as the most plausible mechanism in the genesis of this mosaicism.
Assuntos
Arilsulfatases/genética , Deleção de Genes , Ictiose Ligada ao Cromossomo X/genética , Mosaicismo/genética , Arilsulfatases/deficiência , Feminino , Heterozigoto , Humanos , Esteril-SulfataseRESUMO
The inclusion of a mutation in a pathology-based database such as the Human Gene Mutation Database (HGMD) is a two-stage process: first, the mutation must occur at the DNA level, then it must cause a clinically detectable disease state. The likelihood of the latter step, termed the relative clinical observation likelihood (RCOL), can be regarded as a function of the structural/functional consequences of a mutation at the protein level. Following this paradigm, we modeled in silico all amino acid replacements that could potentially have arisen from an inherited single base pair substitution in five human genes encoding arylsulphatase A (ARSA), antithrombin III (SERPINC1), protein C (PROC), phenylalanine hydroxylase (PAH), and transthyretin (TTR). These proteins were chosen on the basis of 1) the availability of a crystallographic structure, and 2) a sufficiently large number of amino acid replacements being logged in HGMD. A total of 9,795 possible mutant structures were modeled and 20 different biophysical parameters assessed. Together with the HGMD-derived spectra of clinically detected mutations, these data allowed maximum likelihood estimation of RCOL profiles for the 20 parameters studied. Nine parameters (including energy difference between wild-type and mutant structures, accessibility of the mutated residue, and distance from the binding/active site) exhibited statistically significant variability in their RCOL profiles, indicating that mutation-associated changes affected protein function. As yet, however, a biological meaning could only be attributed to the RCOL profiles of solvent accessibility and, for three proteins, local energy change, disturbed geometry, and distance from the active center. The limited ability of the biophysical properties of mutations to explain clinical consequences is probably due to our current lack of understanding as to which amino acid residues are critical for protein folding. However, since the proteins examined here were unrelated, and our findings consistent, it may nevertheless prove possible to extrapolate to other proteins whose dysfunction underlies inherited disease.
Assuntos
Substituição de Aminoácidos/genética , Biofísica/métodos , Doenças Genéticas Inatas/genética , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Antitrombina III/química , Antitrombina III/genética , Antitrombina III/fisiologia , Deficiência de Antitrombina III/genética , Deficiência de Antitrombina III/metabolismo , Arilsulfatases/química , Arilsulfatases/deficiência , Arilsulfatases/genética , Arilsulfatases/fisiologia , Bases de Dados Genéticas , Bases de Dados de Proteínas , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/metabolismo , Genótipo , Humanos , Leucodistrofia Metacromática/enzimologia , Leucodistrofia Metacromática/genética , Modelos Genéticos , Mutação de Sentido Incorreto/genética , Fenótipo , Fenilalanina Hidroxilase/química , Fenilalanina Hidroxilase/deficiência , Fenilalanina Hidroxilase/genética , Fenilalanina Hidroxilase/fisiologia , Fenilcetonúrias/enzimologia , Fenilcetonúrias/genética , Pré-Albumina/química , Pré-Albumina/deficiência , Pré-Albumina/genética , Pré-Albumina/fisiologia , Proteína C/química , Proteína C/genética , Proteína C/fisiologia , Deficiência de Proteína C/genética , Deficiência de Proteína C/metabolismo , Estrutura Secundária de Proteína/genéticaRESUMO
X-linked ichthyosis (XLI) is an inborn error of metabolism due to steroid sulfatase (STS) deficiency. STS assay and FISH are useful in diagnosing carrier status of XLI. Biochemical analysis appears to indicate that most sporadic cases are inherited. Since this method does not seem to be completely reliable in recognizing XLI-carriers, the aim of the present study was to corroborate by FISH whether or not most sporadic cases of XLI had de novo mutations. XLI patients were classified through STS assay and PCR amplification of 5'-3' ends of the STS gene. XLI patients had undetectable levels of STS activity and complete deletion of the STS gene. Patients' mothers were studied through STS assay and FISH. Nine out of 12 mothers presented an STS activity compatible with XLI-carrier state. These mothers also had only one copy of the STS gene, indicating that they carry the primary gene defect. One mother had normal STS activity but only one copy of the STS gene. This data corroborated that most sporadic cases do not represent de novo mutations, and that FISH must be included in the analysis of mothers of sporadic cases when they present with normal STS activity, in order to correctly diagnose the XLI carrier state.
Assuntos
Arilsulfatases/genética , Triagem de Portadores Genéticos , Ictiose Ligada ao Cromossomo X/genética , Arilsulfatases/deficiência , Saúde da Família , Feminino , Humanos , Ictiose Ligada ao Cromossomo X/enzimologia , Hibridização in Situ Fluorescente , Masculino , Esteril-SulfataseAssuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomo X/genética , Anormalidades Múltiplas/enzimologia , Arilsulfatases/deficiência , Arilsulfatases/genética , Criança , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Saúde da Família , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Humanos , Ictiose/enzimologia , Ictiose/genética , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Radiografia , SíndromeRESUMO
BACKGROUND: X-linked ichthyosis (XLI) is an inherited skin disorder caused by a deficiency of steroid sulfatase (STS). The gene and protein of STS were examined in 19 Japanese patients with XLI. RESULTS: In Western blotting analysis, no cross-reacting peptide was detected in the patients' placenta, although a single band (63 kD) corresponding to STS in a normal subject was observed. Southern blotting was performed using EcoRI digests of cellular DNA from 13 XLI patients and full-length human STS cDNA as a probe. Normal males had bands of 20, 15, 10, 9.0, 6.1, 4.2, 2.6, and 1.5 kb. Twelve of the 19 patients had only 20- and 1.5-kb bands. Only one patient had the same band pattern as that of normal males. The STS gene was analyzed by PCR in 6 of the 19 patients. PCR amplification products were sequenced to analyze the STS gene. Two cases with one-base change in the STS gene and variation in amino acids H444R and E560P were found. Mutant STS cDNA was transfected into COS-1 cells and the STS enzyme activity was assayed. The enzyme activities were less than the minimum detection value of the detection system. CONCLUSIONS: These results suggest that XLI is mainly caused by an extensive deletion of the STS gene and that the PCR method is useful for detection of STS point mutations.
Assuntos
Arilsulfatases/deficiência , Arilsulfatases/genética , Deleção de Genes , Genoma , Ictiose Ligada ao Cromossomo X/genética , Erros Inatos do Metabolismo/genética , Animais , Arilsulfatases/metabolismo , Sequência de Bases/genética , Células COS/metabolismo , DNA Complementar/fisiologia , Feminino , Humanos , Ictiose Ligada ao Cromossomo X/metabolismo , Linfócitos/enzimologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Placenta/enzimologia , Mutação Puntual/genética , Gravidez , Esteril-Sulfatase , TransfecçãoRESUMO
BACKGROUND: X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. MATERIALS AND METHODS: STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. RESULTS: No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. CONCLUSION: These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients.