| *300457 | ||||||||||||||||||||||||||||||||||||
| NHS GENE; NHS | ||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: NHS | ||||||||||||||||||||||||||||||||||||
| Cytogenetic location: Xp22.13 Genomic coordinates (GRCh37): X:17,393,542 - 17,754,113 (from NCBI) | ||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||
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| Cloning | ||||||||||||||||||||||||||||||||||||
| By positional cloning in the Nance-Horan syndrome (302350) critical region of the X chromosome and database searching, Burdon et al. (2003) identified and characterized a novel full-length gene, which they designated NHS. The NHS gene encodes 2 mRNA isoforms; the major isoform encodes a deduced 1,630-amino acid protein and the minor isoform encodes a deduced N-terminus truncated 1,335-amino acid protein. By database searching, Burdon et al. (2003) identified NHS orthologs in several species; both the mouse and rat NHS proteins show 76% sequence identity to the human protein. The NHS protein contains 4 conserved nuclear localization signals. Northern blot analysis detected expression of 2 major transcripts of approximately 8.7 kb and 7.7 kb in all human adult and fetal tissues tested. Expression studies in mouse showed that the Nhs gene is broadly expressed throughout brain development. In situ hybridization studies showed that Nhs expression is developmentally regulated in a range of mouse embryonic tissues, including the lens, brain, craniofacial mesenchyme, and dental primordia. Coccia et al. (2009) identified an additional isoform of 1,453 amino acids that is transcribed and translated from exon 1a. They noted that the 1,335-amino acid isoform is transcribed from exon 1b and translated from exon 4. | ||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||
| Burdon et al. (2003) determined that the NHS gene contains 9 exons. Coccia et al. (2009) determined that the NHS gene contains at least 10 exons with alternative splicing of exons 1a and 1b resulting in respective isoforms. | ||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||
| By genomic sequence analysis, Burdon et al. (2003) mapped the NHS gene to chromosome Xp22.13. | ||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||
| In 5 families segregating Nance-Horan syndrome (302350), Burdon et al. (2003) identified mutations in the NHS gene (see 300457.0001-300457.0004). Brooks et al. (2004) studied pedigrees with Nance-Horan syndrome, independently identified the NHS gene first reported by Burdon et al. (2003), and identified truncating mutations in 3 pedigrees. Brooks et al. (2004) identified no mutation in the NHS gene in a family with X-linked congenital cataract (CXN; 302200) that maps to the same region, originally described by Francis et al. (2002), suggesting that Nance-Horan syndrome and this form of X-linked congenital cataract may not be allelic. In affected members of the family reported by van Dorp and Delleman (1979), Florijn et al. (2006) identified a mutation in the NHS gene (300457.0006). Florijn et al. (2006) also identified mutations in the NHS gene in 3 additional NHS families. Van Esch et al. (2007) reported a 10-month old male infant with severe encephalopathy, congenital cataracts, and tetralogy of Fallot who had a hemizygous de novo 2.8-Mb microdeletion at chromosome Xp22.2-Xp22.13, including the CDKL5 (300203) and NHS genes. He had microphthalmia, refractory myoclonic seizures, and hypotonia. The clinical features were consistent with both Nance-Horan syndrome and early infantile epileptic encephalopathy-2 (EIEE2; 300672), which is caused by mutation in the CDKL5 gene. Coccia et al. (2009) performed clinical and molecular analysis of 7 families with NHS and identified 5 protein-truncating mutations and a large deletion encompassing the majority of the NHS gene. In addition, they identified copy number variation of the NHS gene in 2 families with X-linked cataract but without other features of NHS (see below), thus demonstrating that NHS and X-linked cataract are allelic. Coccia et al. (2009) suggested that lack of functional NHS protein causes NHS, whereas aberrant transcription of the NHS gene leads to the milder X-linked cataract phenotype. X-linked Congenital Cataract In a 4-generation family with isolated X-linked congenital cataract (CXN; 302200), originally described by Francis et al. (2002) and negative for mutation in the NHS gene (see Brooks et al., 2004), Coccia et al. (2009) performed array-comparative genomic hybridization (CGH) analysis and found a complex rearrangement consisting of triplication of a region encompassing the NHS, SCML1 (300227), and RAI2 (300217) genes embedded within a duplicated region (300457.0007). Further analysis revealed that 1 copy of the NHS gene lacked exon 1, another copy had all known exons but was disrupted upstream, and a third copy was intact; the 3 copies of the SCML1 and RAI2 genes appeared to be intact. The rearrangement segregated with disease in the family. By array-CGH and sequencing analysis in another family segregating X-linked congenital cataract over 3 generations, Coccia et al. (2009) identified an approximately 4.8-kb deletion (300457.0008) within the large intron 1 of the NHS gene. This deleted interval contains several highly conserved regions, possibly representing potential promoter sequences. Both mutations were predicted to result in altered transcriptional regulation of the NHS gene. | ||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||
| There is suggestive phenotypic and genetic evidence that the mouse Xcat mutant is a model for the Nance-Horan syndrome. Huang et al. (2006) performed sequence and FISH analysis of the Xcat critical region on the X chromosome and detected a large insertion between exons 1 and 2 of the mouse Nhs1 gene. The insertion inhibits expression of the Nhs1 isoform containing exon 1 and results in exclusive expression of the alternative isoform containing exon 1A. Quantitative RT-PCR of Xcat mutant cDNA showed reduced levels of Nhs1 transcripts, and immunohistochemical analysis detected significantly reduced Nhs1 staining in the cytoplasm of elongating lens fiber cells from Xcat mutant neonate mouse lens compared to wildtype. Transient transfection studies in Chinese hamster ovary cells demonstrated that Nhs1 exon 1 is critical for localization to the cytoplasm. Huang et al. (2006) concluded that Nhs1 exon 1 contains crucial information required for proper expression and localization of Nhs1 protein, lack of which results in the abnormal Xcat mouse phenotype. | ||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||
| .0001 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, 1-BP INS, 2387C | ||||||||||||||||||||||||||||||||||||
| In affected members of the extended Australian family in which Horan and Billson (1974) described Nance-Horan syndrome (302350), Burdon et al. (2003) identified a 1-bp insertion in exon 6 of the NHS gene, 2387insC, resulting in a frameshift in the reading frame at codon 796 with a premature stop codon following the addition of 35 amino acids. | ||||||||||||||||||||||||||||||||||||
| .0002 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, 1-BP DEL, 3459C | ||||||||||||||||||||||||||||||||||||
| In affected members of the Australian family with Nance-Horan syndrome (302350) reported by Walpole et al. (1990), Burdon et al. (2003) identified a 1-bp deletion in the NHS gene, 3459delC, resulting in a frameshift at codon 1153. | ||||||||||||||||||||||||||||||||||||
| .0003 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, ARG378TER | ||||||||||||||||||||||||||||||||||||
| In an isolated case of Nance-Horan syndrome (302350), Burdon et al. (2003) identified a de novo 1117C-T transition in the NHS gene, resulting in an arg378-to-ter (R378X) mutation. Florijn et al. (2006) identified the R378X mutation in a patient with Nance-Horan syndrome. | ||||||||||||||||||||||||||||||||||||
| .0004 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, 1-BP INS, 718G | ||||||||||||||||||||||||||||||||||||
| In a mother and daughter with Nance-Horan syndrome (302350), Burdon et al. (2003) identified 2 sequence variations: a 1-bp insertion (718insG) at the first base of exon 3, resulting in a frameshift at codon 240 with a premature stop codon following the addition of 16 amino acids, and an IVS2-3C-G substitution at the 3-prime acceptor splice site. The significance of the latter change was uncertain, but it was not detected in 200 control chromosomes. The daughter displayed an unusually severe ocular phenotype for a female with Nance-Horan syndrome. | ||||||||||||||||||||||||||||||||||||
| .0005 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, GLN39TER [dbSNP:rs104894881] | ||||||||||||||||||||||||||||||||||||
| In a 4-generation family containing 8 affected males with severe ocular findings of Nance-Horan syndrome (302350) but mild nonocular findings, Ramprasad et al. (2005) identified a 115C-to-T mutation in exon 1 of the NHS gene, resulting in conversion of glutamine to a stop codon (Q39X). | ||||||||||||||||||||||||||||||||||||
| .0006 NANCE-HORAN SYNDROME | ||||||||||||||||||||||||||||||||||||
| NHS, IVS3AS, A-G, -2 | ||||||||||||||||||||||||||||||||||||
| In affected members of a family with Nance-Horan syndrome (302350) originally reported by van Dorp and Delleman (1979), Florijn et al. (2006) identified a splice site mutation (IVS3AS-2A-G) in the NHS gene. The mutation was not identified in 220 control alleles. | ||||||||||||||||||||||||||||||||||||
| .0007 CATARACT, CONGENITAL, X-LINKED | ||||||||||||||||||||||||||||||||||||
| NHS, 500-KB TRIPLICATION | ||||||||||||||||||||||||||||||||||||
| In a 4-generation family with isolated X-linked congenital cataract (CXN; 302200), originally described by Francis et al. (2002) and negative for mutation in the NHS gene (see Brooks et al., 2004), Coccia et al. (2009) performed array-comparative genomic hybridization (CGH) analysis and found a complex rearrangement consisting of a 500-kb triplication of a region encompassing the NHS, SCML1 (300227), and RAI2 (300217) genes embedded within a duplicated region (0.2 Mb distal and 0.1 Mb proximal to the embedded triplication). Further analysis revealed that 1 copy of the NHS gene lacked exon 1, another copy had all known exons but was disrupted upstream, and a third copy was intact; the 3 copies of the SCML1 and RAI2 genes appeared to be intact. The rearrangement segregated with disease in the family. The 500-kb triplication was predicted to result in altered transcriptional regulation of the NHS gene. | ||||||||||||||||||||||||||||||||||||
| .0008 CATARACT, CONGENITAL, X-LINKED | ||||||||||||||||||||||||||||||||||||
| NHS, 4.8-KB DEL | ||||||||||||||||||||||||||||||||||||
| By array-CGH and sequencing analysis in a family segregating X-linked congenital cataract (CXN; 302200) over 3 generations, Coccia et al. (2009) identified an approximately 4.8-kb deletion (300457.0008) within the large intron 1 of the NHS gene. This deleted interval contains several highly conserved regions, possibly representing potential promoter sequences. The deletion was predicted to result in altered transcriptional regulation of the NHS gene. | ||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||
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