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At least 19 recordsLinked to original sources
PubMed2006

Analysis of Nsdhl-deficient embryos reveals a role for Hedgehog signaling in early placental development.

The X-linked Nsdhl gene encodes a sterol dehydrogenase involved in cholesterol biosynthesis. Mutations in this gene cause the male lethal phenotypes in human CHILD syndrome and bare patches (Bpa) mice. Affected male embryos for several mutant Nsdhl alleles die in mid-gestation with a thin and poorly vascularized placental labyrinth. The timing and specific abnormalities noted suggest a defect in one or more developmental signaling pathways as a possible mechanism. Here, we examined the possible involvement of the hedgehog signaling pathway in the placental pathology of Nsdhl mutants using a transgenic mouse line (Ptch1(tm1Mps)) that contains a lacZ reporter under the control of the promoter for Ptch1, the gene that encodes the major hedgehog receptor. We demonstrate expression of Ptch1 in allantoic mesoderm of the placenta from wild-type mid-gestation embryos. The evidence suggests that the signaling is induced by Indian hedgehog that is produced by distal (ectoplacental) visceral endoderm cells that migrate into the allantoic mesoderm before embryonic day 10.0. Using a ubiquitously expressed, X-linked lacZ transgene that undergoes normal X-inactivation, we demonstrate that the placental defects in Nsdhl/+ female embryos are non-cell autonomous. Further, affected placentas from mutant Nsdhl(Bpa-8H) male embryos demonstrate markedly decreased or no Ptch1-lacZ staining and no migration of Ihh expressing cells into the developing placenta. These data strongly implicate the hedgehog signaling pathway in the pathogenesis of the placental defects in NSDHL deficiency and provide evidence for a role for the hedgehog pathway in the development of a functional mammalian placenta.

3-Hydroxysteroid Dehydrogenases↗
PubMed2003

NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets.

NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked, male lethal disorder, as well as the mouse mutations bare patches and striated. In the present study, we have investigated the subcellular localization of tagged proteins encoded by wild-type and selected mutant murine Nsdhl alleles using confocal microscopy. In addition to an ER localization commonly found for enzymes of post-squalene cholesterol biosynthesis, we have identified a novel association of NSDHL with lipid droplets, which are endoplasmic reticulum (ER)-derived cytoplasmic structures that contain a neutral lipid core. We further demonstrate that trafficking through the Golgi is necessary for ER membrane localization of the protein and propose a model for the association of NSDHL with lipid droplets. The dual localization of NSDHL within ER membranes and on the surface of lipid droplets may provide another mechanism for regulation of the levels and sites of accumulation of intracellular cholesterol.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme.

NSDHL is a 3beta-hydroxysterol dehydrogenase that is involved in the removal of C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the Nsdhl gene are associated with the X-linked male lethal mouse mutations bare patches (Bpa) and striated (Str), as well as with most cases of human CHILD syndrome. To begin to examine the pathogenesis of these disorders, we have determined that affected male embryos for several Nsdhl alleles die in midgestation, between E10.5 and 13.5, while the majority of affected male embryos for the most severe allele, Nsdhl(Bpa1H), die prior to E9.5. Although no consistent anomalies were identified in affected male embryos themselves, the labyrinth layer of the fetal placenta was always thinner, with fewer fetal vessels and decreased proliferation of labyrinth trophoblast cells. X-inactivation is non-random in females in most lineages of the rodent placenta with preferential inactivation of the paternal X chromosome. For primary defects involving these extraembryonic lineages, heterozygous females with a mutant maternal X chromosome would be expected to have an identical placental phenotype to that found in affected male embryos. We hypothesize that abnormalities in cells of the allantoic mesoderm that undergo random X-inactivation and form the endothelial lining of the fetal vessels of the labyrinth are associated with the male lethality, perhaps through disruption of an as yet unidentified signaling pathway.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome.

We report for the first time that CHILD syndrome (MIM 308050), an X-linked dominant, male-lethal trait characterized by an inflammatory nevus with striking lateralization and strict midline demarcation, as well as ipsilateral hypoplasia of the body is caused by mutations in the gene NSDHL located at Xq28 (NAD(P)H steroid dehydrogenase-like protein) encoding a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway. SSCA and genomic sequence analysis of NSDHL identified in 6 patients with CHILD syndrome, including one boy as well as a mother and her daughter, mutations potentially impairing protein function. This phenotype is distinct from, but shares various clinical and biochemical findings with chondrodysplasia punctata (CDPX2, MIM 302960). CDPX2 is due to mutations affecting a delta8-delta7 sterol isomerase (EBP, emopamil binding protein, at Xp11.22-p11.23) that functions downstream of NSDHL in a later step of cholesterol biosynthesis. EBP was unaffected in the patients analyzed by us demonstrating that CHILD syndrome and CDPX2 are not caused by allelic mutations. Two mouse X-linked dominant male-lethal traits, bare patches (Bpa) and striated (Str) had previously been associated with mutations in Nsdhl. They provide animal models for the study of CHILD syndrome, a further human condition due to mutations in a gene of the cholesterol synthesis pathway.

3-Hydroxysteroid Dehydrogenases↗
PubMed2026

Integrated Bioinformatics Analysis Revealing that the NSDHL Gene Might Be Associated with the Progression of Western HFD/SW-Induced Hepatocellular Carcinoma.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) remains a significant global health concern. However, the etiology and pathogenesis of HCC have yet to be fully elucidated. Previous studies have indicated a close association between obesity and the occurrence and progression of HCC. The objective of this study was to employ bioinformatics strategies in order to explore key genes associated with the clinical diagnosis and prognosis of HCC induced by a Western high-fat diet and sugar water (HFD/SW). MATERIALS AND METHODS: We obtained the expression profile chip data GSE197884 from the Gene Expression Omnibus (GEO) database. Subsequently, “DESeq” and “Limma” R packages were employed to identify differentially expressed genes (DEGs) while constructing a co-expressed gene network using weighted gene co-expression analysis (WGCNA). Functional enrichment analyses were then carried out, followed by the construction of a protein-protein interaction (PPI) network to uncover core genes. The core genes were confirmed through data retrieved from The Cancer Genome Atlas (TCGA) database in order to determine their status as hub genes. Finally, survival and tumor immune infiltration analyses were performed to unveil the prognostic significance of these hub genes. RESULTS: In total, 126 intersection targets were retrieved through the Venn diagram. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the DEGs were primarily related to the proliferation and apoptosis of HCC cells, the digestion and metabolism of liver cells, the HCC tumor microenvironment, and immune response. The PPI network analysis identified 11 core targets, among which seven hub genes, including NSDHL, MVK, SQLW, GCAT, ALAS2, GLDC, and AGXT, were obtained after TCGA database validation. Furthermore, it was found that NSDHL was closely associated with the clinical diagnosis and prognosis of HCC induced by HFD/SW and also affected the cellular immune infiltration in the HCC tumor microenvironment. CONCLUSION: The present study demonstrated a significantly elevated expression of NSDHL in HCC tissues, suggesting its potential as a specific biomarker for precise clinical diagnosis and prognosis assessment of HCC induced by HFD/SW.

Computational Biology↗
PubMedDate not supplied

Identification of two novel mutations in the murine Nsdhl sterol dehydrogenase gene and development of a functional complementation assay in yeast.

Nsdhl is a 3beta-hydroxysterol dehydrogenase that is involved in the removal of C-4 methyl groups in the cholesterol biosynthetic pathway. Mutations in this gene are associated with the X-linked male lethal mouse mutations bare patches (Bpa) and striated (Str) and human CHILD syndrome. We have now detected the missense mutations V53D and A94T in conserved amino acids in two additional Bpa alleles. The latter alters the same amino acid as a missense mutation found in two unrelated CHILD patients, strongly suggesting that differences in the phenotype between Bpa mice and females with CHILD syndrome are unlikely to be explained by different types or sites of mutations. We have also demonstrated that the mouse NSDHL protein can rescue the lethality of erg26 deficient cells of Saccharomyces cerevisiae that lack the yeast ortholog, substantiating the role of NSDHL as a C-3 sterol dehydrogenase. Using this in vivo assay, we have demonstrated that two Str alleles function as hypomorphs, while three Bpa and one Str allele provide no complementation or rescue.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement.

The CHILD syndrome (MIM 308050), an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects, is an X-linked dominant trait with lethality for male embryos. Recently, we elucidated the underlying gene defect by demonstrating point mutations in NSDHL (NAD[P]H steroid dehydrogenase-like protein) at Xq28 in 6 patients with classic CHILD syndrome. The most striking clinical feature is an inflammatory nevus that usually shows a unique lateralization with strict midline demarcation. Ipsilateral defects involve all skeletal structures and internal organs such as the brain, the lung, the heart, or the kidney. As an exception to this rule, in some cases the CHILD nevus may occur in a more or less bilateral distribution. In 1997 Fink-Puches et al described a case of CHILD nevus with an almost symmetric arrangement. To test the correctness of the diagnosis, we now examined blood lymphocytes of this patient by single-strand conformation analysis and genomic sequencing. We identified a novel missense mutation in NSDHL that potentially may impair protein function. We conclude that a diagnosis of CHILD syndrome can be based on clinical features such as the highly characteristic morphology of the CHILD nevus. A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome, and this bilateral involvement should not mislead the clinician to any other diagnosis. Apparently, the effect of random X-inactivation is responsible for different patterns of cutaneous involvement in female carriers of NSDHL mutations.

3-Hydroxysteroid Dehydrogenases↗
PubMed2003

Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene.

Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform nevi, often sharply delimited at the midline, and ipsilateral limb defects. At least two-thirds of cases demonstrate involvement of the right side. Mutations in an essential enzyme of cholesterol biosynthesis, NAD(P)H steroid dehydrogenase-like [NSDHL], have been reported in five unrelated patients with right-sided CHILD syndrome and in a sixth patient with bilaterally, symmetric nevi and mild skeletal anomalies, but not with CHILD syndrome as originally defined. Although all of the molecularly diagnosed cases with the CHILD phenotype to date have had right-sided disease, we report here a novel nonsense mutation (E151X) of NSDHL in an infant with left-sided CHILD syndrome. This result demonstrates that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts.

Seven human disorders of postsqualene cholesterol biosynthesis have been described. One of these, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, results from mutations in the X-linked gene NADH sterol dehydrogenase-like (NSDHL) encoding a sterol dehydrogenase. A series of mutant alleles of the murine Nsdhl gene are carried by bare patches (Bpa) mice, with Bpa(1H) representing a null allele. Heterozygous Bpa(1H) females display skin and skeletal abnormalities in a distribution reflecting random X inactivation, whereas hemizygous male embryos die before embryonic day 10.5. To investigate the molecular basis of defects associated with perturbations in cholesterol biosynthesis, microarray analysis was performed comparing gene expression in embryonic fibroblasts expressing the Bpa(1H) allele versus wild-type (wt) cells. Labeled cDNAs from cells grown in normal serum or lipid-depleted serum (LDS) were hybridized to microarrays containing 22,000 mouse genes. Among 44 genes that showed higher expression in the Bpa(1H) versus wt cells grown in LDS, 11 function in cholesterol biosynthesis, 7 are involved in fatty acid synthesis, 3 (Srebp2, Insig1, and Orf11) encode sterol-regulatory proteins, and 2 (Ldlr and StarD4) are lipid transporters. Of the 21 remaining genes, 16 are known genes, some of which have been implicated previously in cholesterol homeostasis or lipid-mediated signaling, and 5 are uncharacterized cDNA clones.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene.

The X-linked dominant CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is a rare developmental defect characterized by a strictly lateralized inflammatory nevus. In the majority of cases, the right side of the body is affected. Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys. We describe a case of CHILD syndrome involving the left side of the body. Absence of metacarpal, metatarsal and phalangeal bones of the left hand and foot resulted in oligodactyly, with only 3 fingers and 1 toe. An ipsilateral inflammatory epidermal nevus with hyperkeratosis, parakeratosis, acanthosis and perivascular lymphohistiocytic infiltrate was strictly confined to the left half of the patient's body. The phenotype was shown to be associated with a deletion of exons 6-8 of the X-linked NSDHL gene, confirming that CHILD syndrome is due to loss of function of an enzyme involved in cholesterol biosynthesis.

3-Hydroxysteroid Dehydrogenases↗
PubMed2003

Localization of mammalian NAD(P)H steroid dehydrogenase-like protein on lipid droplets.

Mammalian enzymes in late cholesterol biosynthesis have been localized uniformly over the endoplasmic reticulum by enzymatic methods. We report here the first mammalian cholesterol biosynthetic enzyme unequivocally localized at the surface of intracellular lipid storage droplets. NAD(P)H steroid dehydrogenase-like protein (Nsdhl), a mammalian C-3 sterol dehydrogenase involved in the conversion of lanosterol into cholesterol, was localized on lipid droplets by immunofluorescence microscopy and subcellular fractionation. Nsdhl was localized on lipid droplets even when cell growth exclusively depended on cholesterol biosynthesis mediated by this enzyme. Depletion of fatty acids in culture medium reduced the development of lipid droplets and caused Nsdhl redistribution to the endoplasmic reticulum. Elevating oleic acid in medium induced well developed, Nsdhl-positive lipid droplets, and simultaneously caused a reduction in cellular conversion of lanosterol into cholesterol. Manipulated human NSDHL with a missense mutation (G205S) causing a human embryonic developmental disorder, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, could no longer be localized on lipid droplets. Although the expression of wild-type NSDHL could restore the defective growth of a CHO cholesterol auxotroph, LEX2 in cholesterol-deficient medium, the expression of NSDHL(G205S) failed to do so. These results point to functional significance of the localization of Nsdhl on lipid droplets. Functional significance was also suggested by the colocalization of Nsdhl on lipid droplets with TIP47, a cargo selection protein for mannose 6-phosphate receptors from late endosomes to the trans-Golgi network. These results add to the growing notion that the lipid droplet is an organelle endowed with more complex roles in various biological phenomena.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

A novel somatic mutation of the 3beta-hydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma.

OBJECTIVE: To analyze the 3beta-hydroxysteroid dehydrogenase (NSDHL) gene in verruciform xanthoma (VX) to elucidate its potential role in the histogenesis of this lesion. DESIGN: DNA was extracted from paraffin-embedded tissue, followed by polymerase chain reaction amplification of exons 4 and 6 of the NSDHL gene. The polymerase chain reaction products were then directly sequenced and analyzed for the presence of somatic mutations. PATIENTS: Nine lesions of VX from 8 patients and 3 unrelated normal controls were evaluated. RESULTS: Two of 9 VXs (22%) demonstrated a novel somatic missense mutation in exon 6 of the NSDHL gene. The mutation was not present in the remaining 7 lesions of VX, nonlesional internal controls, and 3 unrelated normal controls. No mutation of exon 4 was found in any case. Mutations of exons 4 and 6 previously identified in CHILD syndrome were not seen in our cases. CONCLUSIONS: (1) A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic VXs. (2) Known CHILD syndrome mutations in exons 4 and 6 of the NSDHL gene do not contribute to the histogenesis of sporadic VXs.

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions.

BACKGROUND: CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects, Online Mendelian Inheritance in Man 308050) is an X-linked dominant trait with lethality for male embryos. The disorder is caused by mutations in NSDHL (Online Mendelian Inheritance in Man 300275), a gene playing an important role in the cholesterol biosynthetic pathway. Most reports deal with sporadic cases, and only 5 cases of mother-to-daughter transmission have been documented. We present here a family with mild features of CHILD syndrome in 3 generations. Molecular analysis was used to confirm the diagnosis. OBSERVATIONS: We studied 14 members of a family with CHILD syndrome. The 23-year-old proposita, her mother, 2 aunts, and her grandmother presented with mild or minimal skin lesions that had been present since infancy. Analysis of the NSDHL gene showed missense mutation c.370G-->A in these 5 patients. This mutation was absent in the 9 clinically unaffected family members tested. CONCLUSIONS: In this family, we recognized CHILD syndrome with mild or minimal features in 3 generations because we were able to verify our clinical diagnosis by means of molecular analysis. We assume that many cases that so far have been considered sporadic may in fact be familial when a meticulous physical examination of female family members is combined with molecular testing.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

The gene mutated in bare patches and striated mice encodes a novel 3beta-hydroxysteroid dehydrogenase.

X-linked dominant disorders that are exclusively lethal prenatally in hemizygous males have been described in human and mouse. None of the genes responsible has been isolated in either species. The bare patches (Bpa) and striated (Str) mouse mutations were originally identified in female offspring of X-irradiated males. Subsequently, additional independent alleles were described. We have previously mapped these X-linked dominant, male-lethal mutations to an overlapping region of 600 kb that is homologous to human Xq28 (ref. 4) and identified several candidate genes in this interval. Here we report mutations in one of these genes, Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein, in two independent Bpa and three independent Str alleles. Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis. Our results demonstrate that Bpa and Str are allelic mutations and identify the first mammalian locus associated with an X-linked dominant, male-lethal phenotype. They also expand the spectrum of phenotypes associated with abnormalities of cholesterol metabolism.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

CHILD syndrome avant la lettre.

The CHILD syndrome is an acronymic designation for congenital hemidysplasia with ichthyosiform nevus and limb defects. This X-linked dominant, male-lethal trait is caused by mutations in the gene NSDHL that is localized at Xq28 and involved in cholesterol metabolism. The CHILD nevus that constitutes a hallmark of this multisystem birth defect usually shows a striking lateralization pattern. Until now, a report of Zellweger and Uehlinger from 1948 was believed to represent the first published case of CHILD syndrome. However, we have now found an earlier report published in 1903 by Otto Sachs. An 8-year-old girl had a "xanthoma-like nevus" involving the right axillary region and a congenital muscular weakness of the right upper arm. Sachs described the clinical and histopathological features of CHILD nevus comprehensively, including the characteristic changes of verruciform xanthoma that can be taken within the group of epidermal nevi as a pathognomonic feature of CHILD nevus. This report is the earliest description of CHILD syndrome known so far. Moreover, Sachs presented in this article a comprehensive description of verruciform xanthoma, thus anticipating Shafer's "first report" of this histopathological phenomenon (1971) by almost 70 years.

Axilla↗
PubMed2000

The Conradi-Hünermann-Happle syndrome is caused by mutations in the gene that encodes a 8- 7 sterol isomerase and is biochemically related to the CHILD syndrome.

We here review the clinical and genetic features of the Conradi-Hünermann-Happle syndrome. The disease is characterized by chondrodysplasia punctata, linear ichthyosis, cataract, and short stature. The X-linked dominant mode of inheritance was first recognized by Rudolf Happle in the years 1977 to 1981, who also fully delineated the clinical spectrum of this clinico-genetic entity. In the past, linkage studies had firmly excluded the gene for this syndrome from the Xq28 region, but unfortunately had also failed to clearly map the gene elsewhere on the X-chromosome. Very recently, causative mutations were identified in a large number of patients in the gene for emopamil binding protein. This gene is located on the short arm of Xp11.22-23 and also acts as a D8-D7 sterol isomerase. This enzymatic function plays a crucial role in cholesterol biosynthesis. It is of note that very recent investigations by the Marburg group have disclosed that the CHILD syndrome is likewise caused by a similar metabolic defect, namely a deficiency of a 3b-hydroxysteroid dehydrogenase (NSDHL). In the pathway of cholesterol biosynthesis this enzyme functions "upstream" of D8-D7 sterol isomerase and was shown to underlie the mouse mutant bare patches. Molecular studies in these syndromes now allow us to determine which family members carry the mutation and have already provided evidence in the Conradi-Hünermann-Happle syndrome for both gonadal and somatic mosaicism. As gonadal mosaicism seems to be frequent in this disease, a recurrence risk for further pregnancies has to be considered when dealing with a seemingly sporadic case.

3-Hydroxysteroid Dehydrogenases↗