Novel missense mutation (Arg432Cys) in a patient with steroid sulphatase‐deficiency

González-Huerta, Luz María; Riviera-Vega, M. R.; Kofman-Alfeuro, S. H.; Cuevas-Covarrubias, Sergio A.

doi:10.1046/j.1365-2265.2003.17851.x

Cited by 7 publications

(7 citation statements)

References 14 publications

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“…In 2 brothers there were no abnormal findings in the MLPA analysis and subsequent Sanger sequencing of the STS gene revealed a hemizygous nonsynonymous missense mutation in exon 9 ( Supplemental Figure 1C ) encoding for p.R454C, a cytosine to thymidine change at position g.114,414 resulting in the replacement of arginine to cysteine on the protein level. This mutation has previously been reported in a patient with XLI ( 19 ).…”

Section: Resultssupporting

confidence: 57%

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

Idkowiak¹,

Subtil²,

O’Neil³

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet.Patients and Methods:We carried out a cross-sectional study in 30 males with STSD (age 6–27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing.Results:Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage.Conclusions:In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.

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Section: Resultssupporting

confidence: 57%

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

Idkowiak¹,

Subtil²,

O’Neil³

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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“…Data from the literature seem to indicate that some STS codons are more frequently mutated. In fact, different missense mutations involve codons 372, 454 and 560, and a nonsense mutation has been reported at codon 344 . As shown in Table , 25 point mutations, including those reported in this study, have been identified to date.…”

Section: Discussionmentioning

confidence: 99%

“…Data from the literature seem to indicate that some STS codons are more frequently mutated. In fact, different missense mutations involve codons 372, [38,39] 454 [40,41] and 560, [42,43] and a nonsense mutation has been reported at codon 344. [44] As shown in Table 2 In conclusion, our findings underline once more that, in the absence of an informative family history, the differential diagnosis between ichthyosis vulgaris and XLI may not be trivial because of overlapping phenotypic spectrum.…”

Section: Discussionmentioning

confidence: 99%

X‐linked ichthyosis: Clinical and molecular findings in 35 Italian patients

Diociaiuti

Angioni

Pisaneschi

et al. 2018

Experimental Dermatology

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Recessive X-linked ichthyosis (XLI), the second most common ichthyosis, is caused by mutations in the STS gene encoding the steroid sulfatase enzyme. A complete deletion of the STS gene is found in 85%-90% of cases. Rarely, larger deletions involving contiguous genes are detected in syndromic patients. We report the clinical and molecular genetic findings in a series of 35 consecutive Italian male patients. All patients underwent molecular testing by MLPA or aCGH, followed, in case of negative results, by next-generation sequencing analysis. Neuropsychiatric, ophthalmological and paediatric evaluations were also performed. Our survey showed a frequent presence of disease manifestations at birth (42.8%). Fold and palmoplantar surfaces were involved in 18 (51%) and 7 (20%) patients, respectively. Fourteen patients (42%) presented neuropsychiatric symptoms, including attention-deficit hyperactivity disorder and motor disabilities. In addition, two patients with mental retardation were shown to be affected by a contiguous gene syndrome. Twenty-seven patients had a complete STS deletion, one a partial deletion and 7 carried missense mutations, two of which previously unreported. In addition, a de novo STS deletion was identified in a sporadic case. The frequent presence of palmoplantar and fold involvement in XLI should be taken into account when considering the differential diagnosis with ichthyosis vulgaris. Our findings also underline the relevance of involving the neuropsychiatrist in the multidisciplinary management of XLI. Finally, we report for the first time a de novo mutation which shows that STS deletion can also occur in oogenesis.

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“…The loss of activity does not appear to be caused by incorrect localization or posttranslational modifications but may be due to a shortened half-life and/or loss of the substrate binding site (9). A further six mutations have now been identified, all of which lead to catalytically inactive STS (10,11). To date, all the point mutations reported are located in the carboxyl region of the STS enzyme, which is thought to be important for substrate binding (12).…”

Section: Molecular Biology Of Stsmentioning

confidence: 99%

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

et al. 2005

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Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

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Novel missense mutation (Arg432Cys) in a patient with steroid sulphatase‐deficiency

Cited by 7 publications

References 14 publications

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

X‐linked ichthyosis: Clinical and molecular findings in 35 Italian patients

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

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