HGNC Approved Gene Symbol: NSDHL
SNOMEDCT: 17608003, 773329005;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:152,831,063-152,869,729 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | CHILD syndrome | 308050 | X-linked dominant | 3 |
| CK syndrome | 300831 | X-linked recessive | 3 |
The NSDHL gene encodes NAD(P)H steroid dehydrogenase-like protein, which is a C4 demethylase involved in postsqualene cholesterol biosynthesis (Caldas and Herman, 2003).
Heiss et al. (1996) identified the human NSDHL gene, the homolog of the mouse gene mutant in the 'bare patches' (Bpa) and 'striated' (Str) phenotypes, at Xq28.
McLarren et al. (2010) found expression of the NSDHL gene in developing cortical neurons and glia in both human and mouse and noted that the enzyme localized to the surface of the endoplasmic reticulum and to lipid droplets.
McLarren et al. (2010) noted that the NSDHL gene contains 8 exons.
McLarren et al. (2010) noted that the NSDHL gene maps to chromosome Xq28.
Caldas and Herman (2003) investigated the subcellular localization of wildtype and mutant murine Nsdhl proteins in transfected COS-7 cells using confocal microscopy. In addition to endoplasmic reticulum (ER)- localization commonly found for enzymes of post-squalene cholesterol biosynthesis, the authors identified a novel association of NSDHL with lipid droplets, which are ER-derived cytoplasmic structures containing a neutral lipid core. Trafficking through the Golgi was necessary for ER membrane localization of the protein.
CHILD Syndrome
Konig et al. (2000) analyzed 6 patients with CHILD syndrome (308050) for mutations in the NSDHL gene and in the EBP gene (300205), which functions downstream of NSDHL in a later step of cholesterol biosynthesis. Four of the cases were sporadic, including one in a previously reported 46,XY male (Happle et al., 1996), and 2 were familial cases in a mother and her daughter. No mutations were identified in the EBP gene; however, mutations were identified in the NSDHL gene in all of the patients. The NSDHL mutations included 2 missense mutations (300275.0001-300275.0002) and 2 nonsense mutations (300275.0003-300275.0004). One of these mutations was found in both the mother and daughter and in another patient, although based on their family history and ethnic background, they were highly unlikely to be related. The authors concluded that CHILD syndrome can be added to the list of developmental defects associated with mutations affecting cholesterol synthesis.
In a 37-year-old female with CHILD syndrome including torsional and angular deformities of the limbs, Martinez et al. (2022) reported a novel 3-basepair deletion in the NSDHL gene (c.896_898del), resulting in deletion of the amino acid valine at position 299 (val299del).
CK Syndrome
CK syndrome (300831) is an X-linked recessive mental retardation syndrome associated with seizures, thin body habitus, and cortical malformations. Only males are affected; carrier females are unaffected. In affected members of the original family with CK syndrome reported by du Souich et al. (2009), McLarren et al. (2010) identified a hemizygous mutation in the NSDHL gene (300275.0008). A second affected family, originally reported by Tarpey et al. (2009), was found to have a different mutation (300275.0008). In vitro functional expression studies by McLarren et al. (2010) showed that both mutations acted as temperature-sensitive hypomorphic alleles, resulting in a less severe phenotype than that observed with mutations causing CHILD syndrome. McLarren et al. (2010) suggested that the CK syndrome phenotype resulted mainly from accumulation of toxic methylsterol, not necessarily from cholesterol deficiency.
Associations Pending Confirmation
For discussion of a possible association between variation in the NSDHL gene and susceptibility to migraine without aura, see MGR2 (300125).
Angel et al. (1993) mapped the 'bare patches' (Bpa) and 'striated' (Str) mouse mutations, which behave as X-linked dominant male-lethal mutations, to a region of the X chromosome homologous to human Xq28. Levin et al. (1996) defined several candidate genes in this interval. Liu et al. (1999) reported mutations in one of these genes, Nsdhl, encoding an NAD(P)H steroid dehydrogenase-like protein, in 2 independent Bpa and 3 independent Str alleles. Quantitative analysis of sterols from tissues of affected Bpa mice supported a role for Nsdhl in cholesterol biosynthesis. The results demonstrated that Bpa and Str are allelic mutations and identified the first mammalian locus associated with an X-linked dominant, male-lethal phenotype.
Mutant male embryos for several Nsdhl alleles die in midgestation with placental insufficiency. Cunningham et al. (2010) examined a role of the maternal genotype in such placental pathology. Prepregnancy plasma cholesterol levels were similar between wildtype and Bpa1H/+ dams fed a standard, cholesterol-free diet. However, there was a marked decrease in cholesterol levels between embryonic day (E) 8.5 and E10.5 for both genotypes. There was a significant lag between E11.5 and E13.5 (p = 0.0011) in the recovery of levels in Bpa1H/+ dams to their prepregnancy values. The authors generated transgenic mice that expressed human NSDHL and rescued the male lethality of the Bpa1H null allele. In Bpa1H/+ female embryos where the mutant X chromosome was transmitted from a heterozygous mother or a rescued mutant father, placental areas at E10.5 were 50% less than wildtype. Expression of Nsdhl in trophoblast lineages of the placenta and yolk sac endoderm (which occur only from the maternally inherited allele in a female embryo) had the largest effect on placental area (p less than 0.0001). The maternal genotype had a smaller effect, independent of the fetal genotype (p = 0.024). Cunningham et al. (2010) concluded that there are significant effects of the mother and fetal membranes on pregnancy outcome, and implicated a role for cholesterol homeostasis during human pregnancy.
McLarren et al. (2010) found expression of the NSDHL gene in developing cortical neurons and glia in both human and mouse. Embryonic forebrains from male mice with a loss-of-function Nsdhl allele showed a thin and disorganized cortex with increased numbers of apoptotic cells and decreased cellular proliferation.
Konig et al. (2000) identified 3 patients (1 sporadic and a mother and daughter) with CHILD syndrome (308050) who had a C-to-T transition in exon 4 (314C-T) of the NSDHL gene, predicted to result in an ala105-to-val missense mutation.
Konig et al. (2000) identified a patient with CHILD syndrome (308050) who had a G-to-A transition in exon 6 (613G-A) of the NSDHL gene, predicted to result in a gly205-to-ser missense mutation.
Konig et al. (2000) identified a patient with CHILD syndrome (308050) who had a C-to-T transition in exon 6 (628C-T) of the NSDHL gene, predicted to result in a gln210-to-ter nonsense mutation.
Konig et al. (2000) identified a 46,XY male with CHILD syndrome (308050) who had a C-to-T transition in exon 3 (262C-T) of the NSDHL gene, predicted to result in an arg88-to-ter nonsense mutation.
In an unusual female patient with a symmetric distribution of a CHILD nevus (308050), Konig et al. (2002) found a novel heterozygous mutation (544G-C) in exon 6 of the NSDHL gene resulting in an ala182-to-pro missense mutation (A182P).
In a child with left-sided CHILD syndrome (308050), Hummel et al. (2003) identified a glu151-to-ter (E151X) mutation in the NSDHL gene.
In affected members of a 3-generation family with CK syndrome (300831), Tarpey et al. (2009) and McLarren et al. (2010) identified a hemizygous 1-bp duplication (1098dupT) in the NDSHL gene, resulting in an arg367-to-ser (R367S) substitution, frameshift, and extension of the protein past the native stop codon and into the 3-prime untranslated region. The mutation was not identified in 224 controls. By studies in patient cells, HEK293 cells, and yeast cells, McLarren et al. (2010) showed that the mutant protein was temperature-sensitive: at 30 degrees Celsius, the protein was expressed, folded, localized, and functioned correctly, but at 37 degrees, the protein was improperly folded and degraded, resulting in a loss of function. Affected males and obligate female carriers had normal plasma cholesterol, steroid hormone levels, and lipoprotein profiles, but cultured lymphoblastoid cells expressing the mutation showed sterol aberrations, such as accumulation of 4-methyl sterol intermediates, 4,4-dimethyl sterol intermediates, lathosterol, and desmosterol. Cerebrospinal fluid from an affected individual also showed increased methylsterol levels. McLarren et al. (2010) suggested that the phenotype resulted mainly from the accumulation of toxic methylsterols, not necessarily from cholesterol deficiency.
In affected members of a large 5-generation family of Russian descent with CK syndrome (300831) reported by du Souich et al. (2009), McLarren et al. (2010) identified a hemizygous 3-bp deletion (696delGAA) in exon 7 of the NSDHL gene, resulting in the deletion of residue lys232, which was predicted to disrupt the beta-pleated sheet. The phenotype was characterized by mild to severe mental retardation, infantile seizures, thin body habitus, dysmorphic facial features, and polymicrogyria/pachygyria. Studies in patient cells, HEK293 cells, and yeast cells indicated that the mutant protein was temperature-sensitive: at 30 degrees Celsius, the protein was expressed, folded, localized, and functioned correctly, but at 37 degrees, the protein was improperly folded and degraded, resulting in a loss of function. Affected males and obligate female carriers had normal plasma cholesterol, steroid hormone levels, and lipoprotein profiles, but cultured lymphoblastoid cells expressing the mutation showed sterol aberrations, such as accumulation of 4-methyl sterol intermediates, 4,4-dimethyl sterol intermediates, lathosterol, and desmosterol. Cerebrospinal fluid from an affected individual also showed increased methylsterol levels. McLarren et al. (2010) suggested that the phenotype resulted mainly from the accumulation of toxic methylsterols, not necessarily from cholesterol deficiency.
Angel, T. A., Faust, C. J., Gonzales, J. C., Kenwrick, S., Lewis, R. A., Herman, G. E. Genetic mapping of the X-linked dominant mutations striated (Str) and bare patches (Bpa) to a 600-kb region of the mouse X chromosome: implications for mapping human disorders in Xq28. Mammalian Genome 4: 171-176, 1993. [PubMed: 8439729] [Full Text: https://doi.org/10.1007/BF00352233]
Caldas, H., Herman, G. E. NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. Hum. Molec. Genet. 12: 2981-2991, 2003. [PubMed: 14506130] [Full Text: https://doi.org/10.1093/hmg/ddg321]
Cunningham, D., Talabere, T., Bir, N., Kennedy, M., McBride, K. L., Herman, G. E. Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos. Hum. Molec. Genet. 19: 364-373, 2010. [PubMed: 19880419] [Full Text: https://doi.org/10.1093/hmg/ddp502]
du Souich, C., Chou, A., Yin, J., Oh, T., Nelson, T. N., Hurlburt, J., Arbour, L., Friedlander, R., McGillivray, B. C., Tyshchenko, N., Rump, A., Poskitt, K. J., Demos, M. K., Van Allen, M. I., Boerkoel, C. F. Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus. Am. J. Med. Genet. 149A: 2469-2478, 2009. [PubMed: 19842190] [Full Text: https://doi.org/10.1002/ajmg.a.33071]
Happle, R., Effendy, I., Megahed, M., Orlow, S. J., Kuster, W. CHILD syndrome in a boy. Am. J. Med. Genet. 62: 192-194, 1996. [PubMed: 8882402] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960315)62:2<192::AID-AJMG14>3.0.CO;2-J]
Heiss, N. S., Rogner, U. C., Kioschis, P., Korn, B., Poustka, A. Transcription mapping in a 700-kb region around the DXS52 locus in Xq28: isolation of six novel transcripts and a novel ATPase isoform (hPMCA5). Genome Res. 6: 478-491, 1996. [PubMed: 8828037] [Full Text: https://doi.org/10.1101/gr.6.6.478]
Hummel, M., Cunningham, D., Mullett, C. J., Kelley, R. I., Herman, G. E. Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. Am. J. Med. Genet. 122A: 246-251, 2003. [PubMed: 12966526] [Full Text: https://doi.org/10.1002/ajmg.a.20248]
Konig, A., Happle, R., Bornholdt, D., Engel, H., Grzeschik, K.-H. Mutations in the NSDHL gene, encoding a 3-beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am. J. Med. Genet. 90: 339-346, 2000. [PubMed: 10710235]
Konig, A., Happle, R., Fink-Puches, R., Soyer, H. P., Bornholdt, D., Engel, H., Grzeschik, K.-H. A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J. Am. Acad. Derm. 46: 594-596, 2002. [PubMed: 11907515] [Full Text: https://doi.org/10.1067/mjd.2002.113680]
Levin, M. L., Chatterjee, A., Pragliola, A., Worley, K. C., Wehnert, M., Zhuchenko, O., Smith, R. F., Lee, C. C., Herman, G. E. A comparative transcription map of the murine bare patches (Bpa) and striated (Str) critical regions and human Xq28. Genome Res. 6: 465-477, 1996. [PubMed: 8828036] [Full Text: https://doi.org/10.1101/gr.6.6.465]
Liu, X. Y., Dangel, A. W., Kelley, R. I., Zhao, W., Denny, P., Botcherby, M., Cattanach, B., Peters, J., Hunsicker, P. R., Mallon, A.-M., Strivens, M. A., Bate, R., Miller, W., Rhodes, M., Brown, S. D. M., Herman, G. E. The gene mutated in bare patches and striated mice encodes a novel 3-beta-hydroxysteroid dehydrogenase. Nature Genet. 22: 182-187, 1999. [PubMed: 10369263] [Full Text: https://doi.org/10.1038/9700]
Martinez, R., Pena, C., Quiroga-Carrillo, M., Ordonez-Reyes, C., Rincon, J., Suarez-Obando, F., Nossa, S., Garcia, M. F. Musculoskeletal abnormalities and a novel genomic variant in an adult patient with CHILD syndrome: a case report. Clin. Dysmorph. 31: 162-166, 2022. [PubMed: 35394469] [Full Text: https://doi.org/10.1097/MCD.0000000000000422]
McLarren, K. W., Severson, T. M., du Souich, C., Stockton, D. W., Kratz, L. E., Cunningham, D., Hendson, G., Morin, R. D., Wu, D., Paul, J. E., An, J., Nelson, T. N., and 28 others. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am. J. Hum. Genet. 87: 905-914, 2010. [PubMed: 21129721] [Full Text: https://doi.org/10.1016/j.ajhg.2010.11.004]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]