X‐linked recessive chondrodysplasia punctata: Spectrum of arylsulfatase E gene mutations and expanded clinical variability

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.

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

“…Thus, molecular analysis of ARSE can assist in providing an accurate recurrence risk to the family. Mothers heterozygous for ARSE mutations have not been considered symptomatic, but some have smaller stature than expected [Sheffield et al, 1998;Brunetti-Pierri et al, 2003]. In our patient sample, the difference in heights was not significant between the five mothers who were ARSE heterozygotes and the four whose sons did not have detectable ARSE mutations (Mann-Whitney test, P ¼ 0.17).…”

“…Ophthalmologic abnormalities: cataracts, optic disc atrophy, small optic nerves. [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.…”

“…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 .…”

Identification of Tyrosine Sulfation in Extracellular Leucine-rich Repeat Proteins Using Mass Spectrometry

“…In contrast, arylsulfatase E is found in the Golgi compartment (7). Mutations in this gene cause chondrodysplasia punctata, a congenital disorder characterized by abnormalities in cartilage and bone development (7)(8)(9)(10)(11)(12).…”

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

“…5 In these experiments, all missense alleles had negligible activity. 9,10 Considering the phenotypic resemblance of warfarin embryopathy in early gestation to BCP, Franco et al 5 (1995) demonstrated that ARSE activity is inhibited in the presence of warfarin, an anticoagulant drug that decreases amounts of active vitamin K. These findings suggested that cases of BCP without ARSE mutations could be caused by inhibition of a normal ARSE enzyme in fetal development by reducing levels of vitamin K. Because placental transport of vitamin K is normally reduced, 11 vitamin K deficiency in the mother would be expected to result in greater vitamin K deficiency in the fetus. This hypothesis is attractive given that there have been several reports of BCP in offspring of both sexes in which gestational vitamin K deficiency was suspected, including mothers with severe hyperemesis gravidarum, 12 small-intestinal obstruction, 13 small-bowel syndrome, 14 pancreatitis, 15 or biliary lithiasis.…”