Alternative titles; symbols
HGNC Approved Gene Symbol: ARSL
Cytogenetic location: Xp22.33 Genomic coordinates (GRCh38): X:2,934,521-2,968,245 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.33 | Chondrodysplasia punctata, X-linked recessive | 302950 | X-linked recessive | 3 |
Franco et al. (1995) cloned the genomic region within Xp22.3 where the locus for X-linked recessive chondrodysplasia punctata (CDPX1; 302950) had been located and isolated 3 adjacent genes showing highly significant homology to the sulfatase gene family: arylsulfatase D (ARSD; 300002), arylsulfatase L (ARSL; formerly arylsulfatase E, ARSE), and arylsulfatase F (ARSF; 300003). Franco et al. (1995) identified the putative initiation codon of ARSE at nucleotide 68 and the first in-frame stop codon (TGA) at nucleotide 1835, resulting in a predicted protein of 590 amino acids. ARSD lies telomeric to ARSE and both are transcribed toward the telomere. The authors noted that ancient duplications may be responsible for the contiguous location of genes of closely similar sequence and structure. Similar duplications are thought to account for the homologous loci MIC2 (313470), MIC2R (see 313470), and PBDX (314700) in the pseudoautosomal region.
By transfection of the ARSE full-length cDNA in COS-7 cells, Daniele et al. (1998) established 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.
Franco et al. (1995) found that expression of the ARSE gene in COS cells resulted in a heat-labile arylsulfatase activity that was inhibited by warfarin.
Meroni et al. (1996) reported that ARSD and ARSE have several typical features of genes that map in the pseudoautosomal region of the X chromosome: they escape X inactivation, have homologs on the Y chromosome, and are not conserved in mouse. Meroni et al. (1996) noted that ARSD, ARSE, and STS have a conserved gene structure; alignment of the genomic structures revealed perfect conservation of the intron-exon junctions. Sequence analysis of the Y-linked homologs of ARSD and ARSE indicated that they represent truncated pseudogenes.
Franco et al. (1995) detected 11 exons in the ARSE gene.
Franco et al. (1995) identified point mutations in the ARSE gene in 5 patients with CDPX1 (300180.0001-300180.0005). Franco et al. (1995) demonstrated a deficiency of a heat-labile arylsulfatase activity in patients with deletions spanning the CDPX1 region. Thus, Franco et al. (1995) determined that CDPX1 is caused by an inherited deficiency of a novel sulfatase. It is likely that warfarin embryopathy involves drug-induced inhibition of the same enzyme. Another member of the arylsulfatase family, steroid sulfatase (STS; 300737), is deficient in X-linked ichthyosis (308100). ARSA (607574) is deficient in metachromatic leukodystrophy (250100); ARSB (611542) is deficient in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; 253200).
The mutation search by Franco et al. (1995) that uncovered a different mutation in each of 5 patients involved a total of 27 unrelated males with CDPX1. The authors suggested that since only 9 of the 11 exons of the ARSE gene were screened for mutations, additional mutations may be found in the remaining 2 exons (exons 1 and 2). Furthermore, Franco et al. (1995) granted the possibility that mutations in the ARSD or ARSF genes may also cause CDPX1. The identity of the natural substrate for ARSE remained to be determined.
Daniele et al. (1998) introduced 5 missense mutations found in CDPX1 patients into wildtype ARSE cDNA by site-directed mutagenesis. These mutants were transfected into COS-7 cells, and the arylsulfatase activity and biochemical properties were determined. One of the mutants behaved as the wildtype protein. All 4 of the other mutations resulted in complete lack of arylsulfatase activity, although the substitutions did not appear to affect the stability and subcellular localization of the protein.
Matos-Miranda et al. (2013) reported the results of a Collaboration Education and Test Translation (CETT) program for CDPX1 from 2008 to 2010. Of 29 male probands identified, 17 had ARSE mutations (58%) including 10 novel missense alleles and 1 single-codon deletion. All mutant alleles had negligible ARSE activity, and there were no obvious genotype-phenotype correlations. Maternal etiologies were not reported in most patients.
In a girl with CDPX1, Woods et al. (2022) identified homozygosity for a deletion-insertion mutation (c.1227_1228delinsAT, NM_000047.2) in the ARSL gene, resulting in a ser41-to-cys (S41C) substitution. Her mother was heterozygous for the variant. A single-nucleotide polymorphism array suggested segmental uniparental disomy, due to either a postzygotic mechanism due to crossover between X-chromatids, or more likely, a trisomic rescue with loss of the paternal X after a maternal meiosis I error, with later crossover. The phenotype in this patient was milder than that seen in her affected brother; the authors hypothesized that this was due to residual activity of the mutated protein and the ARSE gene escaping X inactivation.
In a male with X-linked chondrodysplasia punctata (CDPX1; 302950), Franco et al. (1995) found a G-to-C transversion in exon 2 of the ARSE gene, resulting in an arg12-to-ser amino acid substitution.
Daniele et al. (1998) found that an R12S construct expressed in COS-7 cells exhibited arylsulfatase activity comparable to wildtype.
Using SSCP analysis followed by sequencing in material from a male with chondrodysplasia punctata (CDPX1; 302950), Franco et al. (1995) found a G-to-A transition in exon 4 of the ARSE gene, resulting in a gly117-to-arg amino acid substitution.
Using SSCP analysis followed by sequencing to study DNA from a male with chondrodysplasia punctata (CDPX1; 302950), Franco et al. (1995) demonstrated a G-to-C transversion in exon 4 of the ARSE gene, resulting in an arg111-to-pro amino acid substitution.
In a male patient who was case 1 in the report by Maroteaux (1989), Franco et al. (1995) found a G-to-T transversion in exon 4 of the ARSE gene, resulting in a gly137-to-val amino acid substitution. Maroteaux (1989) was particularly impressed with hypoplasia of the distal phalanges, and designated the disorder chondrodysplasia punctata, brachytelephalangic.
In a male patient with chondrodysplasia punctata (CDPX1; 302950), Franco et al. (1995) used SSCP analysis followed by sequencing and identified a G-to-C transversion in exon 5 of the ARSE gene, leading to a gly245-to-arg amino acid substitution.
Parenti et al. (1997) identified a cys492-to-tyr (C492Y) mutation in the ARSE gene in an infant with X-linked chondrodysplasia punctata (CDPX1; 302950) who presented at birth with cranial and facial anomalies and short stature, and, by x-ray, punctate calcifications and striking hand and foot abnormalities.
In an Asian newborn who presented with chondrodysplasia punctata (CDPX1; 302950), facial dysmorphisms, cataracts, and neonatal death, Brunetti-Pierri et al. (2003) identified a 2034C-T transition in exon 4 of the ARSE gene, resulting in a pro578-to-ser (P578S) substitution. Expression of the mutation in COS-7 cells showed greatly decreased activity.
In 4 unrelated patients with chondrodysplasia punctata (CDPX1; 302950), Brunetti-Pierri et al. (2003) identified a 2045G-A transition in exon 10 of the ARSE gene, resulting in a trp581-to-ter (W581X) substitution. The authors noted that the W581X mutation seemed to be the most prevalent among patients with identified mutations of the ARSE gene.
Brunetti-Pierri, N., Andreucci, M. V., Tuzzi, R., Vega, G. R., Gray, G., McKeown, C., Ballabio, A., Andria, G., Meroni, G., Parenti, G. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am. J. Med. Genet. 117A: 164-168, 2003. [PubMed: 12567415] [Full Text: https://doi.org/10.1002/ajmg.a.10950]
Daniele, A., Parenti, G., d'Addio, M., Andria, G., Ballabio, A., Meroni, G. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata. Am. J. Hum. Genet. 62: 562-572, 1998. [PubMed: 9497243] [Full Text: https://doi.org/10.1086/301746]
Franco, B., Meroni, G., Parenti, G., Levilliers, J., Bernard, L., Gebbia, M., Cox, L., Maroteaux, P., Sheffield, L., Rappold, G. A., Andria, G., Petit, C., Ballabio, A. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 81: 15-25, 1995. [PubMed: 7720070] [Full Text: https://doi.org/10.1016/0092-8674(95)90367-4]
Maroteaux, P. Brachytelephalangic chondrodysplasia punctata: a possible X-linked recessive form. Hum. Genet. 82: 167-170, 1989. [PubMed: 2722194] [Full Text: https://doi.org/10.1007/BF00284052]
Matos-Miranda, C., Nimmo, G., Williams, B., Tysoe, C., Owens, M., Bale, S., Braverman, N. A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies. Genet. Med. 15: 650-657, 2013. [PubMed: 23470839] [Full Text: https://doi.org/10.1038/gim.2013.13]
Meroni, G., Franco, B., Archidiacono, N., Messali, S., Andolfi, G., Rocchi, M., Ballabio, A. Characterization of a cluster of sulfatase genes on Xp22.3 suggests gene duplications in an ancestral pseudoautosomal region. Hum. Molec. Genet. 5: 423-431, 1996. [PubMed: 8845834] [Full Text: https://doi.org/10.1093/hmg/5.4.423]
Parenti, G., Buttitta, P., Meroni, G., Franco, B., Bernard, L., Rizzolo, M. G., Brunetti-Pierri, N., Ballabio, A., Andria, G. X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene. Am. J. Med. Genet. 73: 139-143, 1997. [PubMed: 9409863] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971212)73:2<139::aid-ajmg7>3.0.co;2-p]
Woods, E., Yates, M., Kanani, F., Balasubramanian, M. Uniparental disomy as a mechanism for X-linked chondrodysplasia punctata. Clin. Dysmorph. 31: 132-135, 2022. [PubMed: 35256563] [Full Text: https://doi.org/10.1097/MCD.0000000000000419]