X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene
Department of Pediatrics, Federico II University, Naples, Italy.American Journal of Medical Genetics (Impact Factor: 3.23). 01/1998; 73(2):139-43. DOI: 10.1002/(SICI)1096-8628(19971212)73:2<139::AID-AJMG7>3.0.CO;2-P
Chondrodysplasia punctata (CP) is a heterogeneous group of bone dysplasias that are characterized by abnormal calcium deposition in areas of enchondral bone formation. The existence of an X-linked recessive form of chondrodysplasia punctata (CDPX) has been recognized in patients who are nullisomic for the Xp22.3 region, presenting with complex phenotypes. The gene of CDPX has been identified recently, and five point mutations of the gene, named ARSE, have been described. Here, we report on the clinical and molecular characterization of a patient with CDPX. The patient presented at birth with cranial and facial anomalies and short stature; an x-ray skeletal survey showed punctate calcifications and striking hand and foot abnormalities. Single strand conformation polymorphism (SSCP) and sequence analysis of the patient's DNA allowed the identification of a new mutation of the ARSE gene; this mutation causes an amino acid substitution from cysteine to tyrosine at position 492 of the ARSE predicted protein product. The clinical description of patients with CDPX due to known mutation of the ARSE is of interest for the precise delineation of the clinical spectrum of the disease.
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- "The analysis was repeated on buccal cells to exclude somatic mosaicism as a cause of the lack of a clinical phenotype. To date there is only a limited number of studies reporting ARSE mutation analysis in patients with a CDPX1 phenotype [Franco et al., 1995; Parenti et al., 1997; Sheffield et al., 1998; Dahl et al., 1999; Brunetti-Pierri et al., 2003; Nino et al., 2008]. Overall, mutations were found in 31 patients, but only in 10 cases mutation analysis was performed also in patients' mothers [Sheffield et al., 1998; Dahl et al., 1999; Nino et al., 2008]. "
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.
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- "Other systems involved: intracranial hemorrhage, hydrocephaly 2 , supendymal cysts 2 , basal ganglia ischemia 1 , hypogammaglobulinemia 2 , hypothyroidism 2 , joint contractures, joint laxity 2 . b This article, P1–P7 [Franco et al., 1995; Parenti et al., 1997; Sheffield et al., 1998; Dahl et al., 1999, (follow-up on patient reported by Franco); Brunetti-Pierri et al., 2003; Wolpoe et al., 2004 ( patient P2 in this manuscript ) ; Garnier et al. , 2006 ] . and the absence of the allele in a population of normal controls . "
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.
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- "Single nucleotide changes that produce the amino acid substitutions R12S, R111P, G137V, G245R, and C492Y were identified in patients affected with CDPX (Franco et al. 1995; Parenti et al., 1997). To investigate the effect of these missense mutations, the nucleotide changes leading to these amino acid substitutions were introduced into the wild-type ARSE expression vector by site-directed mutagenesis. "
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.
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