Mutational spectrum of NSDHL in CHILD syndrome

Bornholdt, Dorothea; König, Arne; Happle, Rudolf; Leveleki, Leonóra; Bittar, Mario; Danarti, Retno; Vahlquist, Anders; Tilgen, Wolfgang; Reinhold, U; Baptista, A. Poiares; Grosshans, É; Vabres, P.; Niiyama, S.; Sasaoka, Kuninori; Tanaka, Toshihiro; Meiss, A L; Treadwell, P A; Lambert, Deborah; Camacho, Francisco Gómez; Kh, Grzeschik

doi:10.1136/jmg.2004.024448

Cited by 70 publications

(106 citation statements)

References 28 publications

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“…The function of NSDHL as a C-4 sterol dehydrogenase was substantiated by the accumulation of 4-methyl and 4,4-dimethyl sterol intermediates in tissue samples and cultured skin fi broblasts from heterozygous Bpa/Str mutant females ( 271 ). In addition, the mouse NSDHL protein can rescue the conditional lethality of S. cerevisiae that lack the ortholreduction defects ( 245,257,258 ) ( Fig. 6E,F ).…”

Section: Gene Identifi Cation and Molecular Biologymentioning

confidence: 91%

“…As noted above, survival of males with a CDPX2-like few surviving females, although intelligence is usually normal. Documented CNS malformations are present in only a small number of cases ( р 10%) ( 258,267 ). The most common abnormalities are hypoplasia of the involved side of the brain and/or cranial nerve involvement.…”

mentioning

confidence: 99%

“…However, in the cases reported since 2000 with NSDHL mutations ( 258,(268)(269)(270), a single instance of hypoplastic left heart syndrome was noted in the newborn with CNS malformations who died ( 268 ). Three of 23 (13%) patients reported by Bornholdt et al ( 258 ) had unilateral renal agenesis.…”

mentioning

confidence: 99%

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Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

399

440

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Section: Gene Identifi Cation and Molecular Biologymentioning

confidence: 91%

mentioning

confidence: 99%

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Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

399

440

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“…To confirm deletions identified by high resolution-array CGH, affecting the gene PORCN and flanking genes on Xp11.23 such as EBP, the copy number of coding PORCN and EBP exons of GG25 and GG26 (PORCN only), was determined by Multiplex Amplifiable Probe Hybridisation (MAPH) as described previously (Bornholdt et al, 2005). Microdeletions in genomic DNA from patients GG36 and GG37 encompassing at least the genes PORCN and EBP were detected by MAPH only (Table 1).…”

Section: Maphmentioning

confidence: 99%

PORCNmutations in focal dermal hypoplasia: coping with lethality

et al. 2009

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The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with ConradiHünermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since E619 PORCN Mutations in FDHno functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status. ©2009Wiley-Liss, Inc.

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“…In animals, deficiency in 3bHSD/D and the C4-demethylation process is lethal for the embryo (Kö nig et al, 2000). Mutations in the corresponding ortholog Nsdhl gene are associated with the X-linked, male-lethal dominant mutations bare patches (Bpa) and striated (Str) in mouse (Liu et al, 1999) and cause the embryo-lethal CHILD syndrome in humans (Bornholdt et al, 2005). Remarkably, mutants of plants deficient in 3bHSD/D and C4-demethylation have not been reported so far, possibly reflecting the vital importance of this pathway-specific step.…”

mentioning

confidence: 99%

Homology Modeling and Site-Directed Mutagenesis Reveal Catalytic Key Amino Acids of 3β-Hydroxysteroid-Dehydrogenase/C4-Decarboxylase from Arabidopsis

et al. 2009

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Sterols become functional only after removal of the two methyl groups at C4 by a membrane-bound multienzyme complex including a 3b-hydroxysteroid-dehydrogenase/C4-decarboxylase (3bHSD/D). We recently identified Arabidopsis (Arabidopsis thaliana) 3bHSD/D as a bifunctional short-chain dehydrogenase/reductase protein. We made use of three-dimensional homology modeling to identify key amino acids involved in 4a-carboxy-sterol and NAD binding and catalysis. Key amino acids were subjected to site-directed mutagenesis, and the mutated enzymes were expressed and assayed both in vivo and in vitro in an erg26 yeast strain defective in 3bHSD/D. We show that tyrosine-159 and lysine-163, which are oriented near the 3b-hydroxyl group of the substrate in the model, are essential for the 3bHSD/D activity, consistent with their involvement in the initial dehydrogenation step of the reaction. The essential arginine-326 residue is predicted to form a salt bridge with the 4a-carboxyl group of the substrate, suggesting its involvement both in substrate binding and in the decarboxylation step. The essential aspartic acid-39 residue is in close contact with the hydroxyl groups of the adenosine-ribose ring of NAD + , in good agreement with the strong preference of 3bHSD/D for NAD + . Data obtained with serine-133 mutants suggest close proximity between the serine-133 residue and the C4b domain of the bound sterol. Based on these data, we propose a tentative mechanism for 3bHSD/D activity. This study provides, to our knowledge, the first data on the three-dimensional molecular interactions of an enzyme of the postoxidosqualene cyclase sterol biosynthesis pathway with its substrate. The implications of our findings for studying the roles of C4-alkylated sterol precursors in plant development are discussed.

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Mutational spectrum of NSDHL in CHILD syndrome

Cited by 70 publications

References 28 publications

Malformation syndromes caused by disorders of cholesterol synthesis

Malformation syndromes caused by disorders of cholesterol synthesis

PORCNmutations in focal dermal hypoplasia: coping with lethality

Homology Modeling and Site-Directed Mutagenesis Reveal Catalytic Key Amino Acids of 3β-Hydroxysteroid-Dehydrogenase/C4-Decarboxylase from Arabidopsis

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