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

Abstract

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.

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…Here, we identified three protein coding genes that displayed a significant inverse correlation between expression and copy number and showed more frequent deletions than gains and/or amplification: NSDHL, EIF4E3 and RFX1. Interestingly, germline mutations of NSDHL cause congenital hemidysplasia ichthyosiform eithroderma and limb defect (CHILD) syndrome [53]. RFX1 has been implicated in transcriptional downregulation of the proto-oncogene c-myc and shown to be epigenetically silenced in human glioma cell lines and tissues [54].…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…Conradi-Hünermann-Happle (CDPX2) and CHILD syndrome are both caused by an enzyme defect within the distal cholesterol biosynthetic pathway as a result of X-linked dominant mutations in the EBP (CDPX2) and NSDHL (CHILD) genes, respectively. 84,146 However, CDPX2 may present with severe CIE or collodion membrane and is therefore regarded as an ichthyosis (Fig 4, F ). 147 Darier disease 148,149 and HaileyeHailey disease 150 are autosomal dominant genodermatoses 151,152 The typical lesions of Darier diseaseeusually beginning in adolescenceeare tiny keratotic papules with a firmly adherent keratin cap, and are most often found on the seborrheic areas, scalp, and extremities; generalized involvement is very rare.…”

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…The loss of brain asymmetry observed in mouse mutants with ciliary dyskinesia (Kawakami et al, 2008) is not observed in human patients (Kennedy et al, 1999;Tanaka et al, 1999;McManus et al, 2004;Afzelius and Stenram, 2006). Another way in which mouse developmental genetics seems to differ with that of human embryos concerns the LR-bilateral separation of pigmentation patterns in CHILD syndrome that occurs in man (Happle, 2002(Happle, , 2006 but is highly mosaic in mice, even though all of the other important features of this disease are present (Konig et al, 2000). The difference here may be profound precisely because a clean midline separation resulting from a nondisjunction/inactivation event at very early cleavage stages (as observed in bird gynandromorphs [Hutt, 1949;Agate et al, 2003;Levin, 2006]) suggests an extremely early origin of the midline, which may be true in many amniotes but not in mice.…”