title: A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies.
abstract: OBJECTIVE
  The only known genetic cause of brachytelephalangic chondrodysplasia punctata is X-linked chondrodysplasia punctata 1 (CDPX1), which results from a deficiency of arylsulfatase E (ARSE). Historically, ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases.
  
  
  METHODS
  To further evaluate causes of brachytelephalangic chondrodysplasia punctata, we established a Collaboration Education and Test Translation program for CDPX1 from 2008 to 2010. Of the 29 male probands identified, 17 had ARSE mutations that included 10 novel missense alleles and one single-codon deletion. To determine pathogenicity of these and additional missense alleles, we transiently expressed them in COS cells and measured arylsulfatase E activity using the artificial substrate, 4-methylumbelliferyl sulfate. In addition, clinical data were collected to investigate maternal effects and genotype-phenotype correlations.
  
  
  RESULTS
  In this study, 58% of males had ARSE mutations. All mutant alleles had negligible arylsulfatase E activity. There were no obvious genotype-phenotype correlations. Maternal etiologies were not reported in most patients.
  
  
  CONCLUSIONS
  CDPX1 is caused by loss of arylsulfatase E activity. Around 40% of male patients with brachytelephalangic chondrodysplasia punctata do not have detectable ARSE mutations or known maternal etiological factors. Improved understanding of arylsulfatase E function is predicted to illuminate other etiologies for brachytelephalangic chondrodysplasia punctata.
authors.affiliation: Department of Human Genetics, Montreal Children's Hospital Research Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Matos-Miranda
authors.forename: Graeme
authors.initials: G
authors.lastname: Nimmo
authors.forename: Bradley
authors.initials: B
authors.lastname: Williams
authors.forename: Carolyn
authors.initials: C
authors.lastname: Tysoe
authors.forename: Martina
authors.initials: M
authors.lastname: Owens
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
mesh_terms: D000483:Alleles; D000818:Animals; D001192:Arylsulfatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002806:Chondrodysplasia Punctata / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D040181:Genetic Diseases, X-Linked / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011446:Prospective Studies; D019655:Quantitative Trait, Heritable
chemical_list: C110155:ARSL protein, human; D001192:Arylsulfatases