Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata.

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 ARS-E, and ARS-F).9 Missense mutations in the ARS-E gene were present in five patients with CDPX, strongly suggesting that CDPX is caused by arylsulphatase E deficiency. No families were studied however. We have tested 16 males and two females who have symmetrical CDP for the presence of mutations in the coding regions of the ARS-D and ARS-E genes. We report the clinical findings, identification, and segregation of three novel mutations in the ARS-E gene in three families with symmetrical CDP. Materials and methods PATIENTSThe 16 males and two females with symmetrical SCDP analysed in this study all had the diagnosis made by showing puncta radiologically. They had been part of a previous study of the classification of SCDP by Sheffield et a3 ' and six of these males had been analysed, but no mutations found, by SSCP for ARS-D and ARS-E mutations in the initial study that defined ARS-E as the causative mutation in CDP.9 Brachytelephalangic CDP was not classified separately from SCDP because we had previously concluded that they were the same entity.

Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

“…Although the extent of the genomic deletions has not been determined, the phenotype of patients with deletions was not markedly different from the group overall. Of the four missense alleles detected in this study, two were previously described, Gly137Ala and Pro578Ser [Sheffield et al, 1998;Brunetti-Pierri et al, 2003]. Expression studies in COS7 cells using the 4-MU substrate were carried out for Pro578Ser and the related allele, Gly137Val, and these were shown to have reduced activities .…”

“…From this group, around one fourth were associated with Xp deletions or rearrangements noted on karyotype analysis. Of the remainder, a total of 56 male probands that met clinical criteria for this disorder have undergone ARSE mutation analysis with mutations identified in 23 [Franco et al, 1995;Parenti et al, 1997;Sheffield et al, 1998;BrunettiPierri et al, 2003;Garnier et al, 2007]. That mutations in ARSE were not identified in the majority of patients evaluated implies genetic heterogeneity, the inclusion of phenocopies or possibly, undetected mutations in ARSE.…”

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

“…Similarly, nine mothers of previously reported males with CDPX1 who had carrier testing were found to be carriers. 3,25,27 Maternal carriers were identified among both ARSE deletion and point mutation alleles (see Table 2). We suggest that the high frequency of maternal carriers, if proven, could be secondary to de novo mutations occurring more often in the germline of the maternal grandfather.…”

“…We performed functional analysis on the 12 novel missense alleles, the single codon deletion identified in our cohort, and 7 novel missense alleles reported previously in which functional analysis had not been done 3,5,25,26 (Table 2). These 20 ARSE alleles were engineered by site-directed mutagenesis and coexpressed in COS1 cells with Renilla luciferase to control for transfection efficiency.…”

“…ARSD has been sequenced in some patients with BCP previously without mutations reported. 5,25 Improved understanding of ARSE function would help to identify additional pathway proteins that, when defective, could be candidates for causing BCP.…”