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Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M, Nishihira Y, Miyashita A, Fujiwara H, Oyama T, Nogovicina A, Sukhomyasova A, Potapova S, Kuwano R, Takahashi H, Nishizawa M, Onodera O - J. Med. Genet. (2010)

Bottom Line: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene.Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state.None of the 203 normal Yakuts individuals had this substitution in the homozygous state.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Yakut Scientific Center of Complex Medical Problems, Siberian Department of Russian Academy of Medical Science, Yakutsk, Russia.

ABSTRACT

Background: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome.

Aims: To identify a causative gene for SOPH syndrome.

Methods: Genomewide homozygosity mapping was conducted in 33 patients in 30 families.

Results: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome.

Conclusion: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

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Related in: MedlinePlus

Haplotype of NBAS mutant chromosome and multiple alignment of NBAS (neuroblastoma amplified sequence) protein. (A) Haplotype of NBAS mutant chromosome for family 17 with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) syndrome and chromatograms of the mutation in the NBAS gene. Disease associated haplotype is boxed. Five nucleotide substitutions, 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; and 3026G→C (resulting in the amino acid substitution C1009S) in exon 26 in NBAS, were observed in a patient and her father in the homozygous state. 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 alteration is observed only in the patient. (B) Amino acid sequence alignment of Homo sapiens NBAS (GenBank accession number NP_056993.2) with orthologs from Pan troglodytes (XP_001161679.1), Canis familiaris (XP_540088.2), Gallus gallus (XP_419959.2), and Danio rerio (NP_001038272.1) revealed by the ClustalW program (http://www.ebi.ac.uk/Tools/clustalw/). Conserved amino acid residues are shaded (GeneDoc program, http://www.nrbsc.org/gfx/genedoc/). Each shade represents a degree of conservation (black, 100%; dark grey, 80%; and grey, 60%). The mutated amino acid R1914H was highly conserved from human to fish, whereas Q44E, V949L, and C1009S were less conserved than R1914H. An amino acid homology search was conducted using the standard protein–protein BLAST. An amino acid sequence of human NBAS (GenBank accession number NP_056993.2), chimpanzee NBAS (XP_001161679.1), dog NBAS (XP_540088.2), chicken NBAS (XP_419959.2), and fish NBAS, (NP_001038272.1) were multiply aligned by the ClustalW program, version 1.83 with default parameters.
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fig5: Haplotype of NBAS mutant chromosome and multiple alignment of NBAS (neuroblastoma amplified sequence) protein. (A) Haplotype of NBAS mutant chromosome for family 17 with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) syndrome and chromatograms of the mutation in the NBAS gene. Disease associated haplotype is boxed. Five nucleotide substitutions, 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; and 3026G→C (resulting in the amino acid substitution C1009S) in exon 26 in NBAS, were observed in a patient and her father in the homozygous state. 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 alteration is observed only in the patient. (B) Amino acid sequence alignment of Homo sapiens NBAS (GenBank accession number NP_056993.2) with orthologs from Pan troglodytes (XP_001161679.1), Canis familiaris (XP_540088.2), Gallus gallus (XP_419959.2), and Danio rerio (NP_001038272.1) revealed by the ClustalW program (http://www.ebi.ac.uk/Tools/clustalw/). Conserved amino acid residues are shaded (GeneDoc program, http://www.nrbsc.org/gfx/genedoc/). Each shade represents a degree of conservation (black, 100%; dark grey, 80%; and grey, 60%). The mutated amino acid R1914H was highly conserved from human to fish, whereas Q44E, V949L, and C1009S were less conserved than R1914H. An amino acid homology search was conducted using the standard protein–protein BLAST. An amino acid sequence of human NBAS (GenBank accession number NP_056993.2), chimpanzee NBAS (XP_001161679.1), dog NBAS (XP_540088.2), chicken NBAS (XP_419959.2), and fish NBAS, (NP_001038272.1) were multiply aligned by the ClustalW program, version 1.83 with default parameters.

Mentions: In the critical region, there were two genes: neuroblastoma-amplified sequence gene (NBAS, MIM 608025) and DEAD (asp-Glu-Ala-Asp) box polypeptide 1 (DDX1) gene (figure 4B). We performed sequence analysis of NBAS and DDX1 in the patients using a series of intronic primers to amplify the coding exons and exon–intronic junctions in the NBAS and DDX1 genes. We found no mutation in DDX1, whereas we identified six nucleotide substitutions in the NBAS gene in the homozygous state in 33 of 34 patients; 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; 3026G→C (resulting in the amino acid substitution C1009S) in exon 26; and 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 (table 2). To exclude the possibility of the presence of heterozygous deletions, we analysed both parents in 10 families and found true homozygosity in all cases. Among these families, in family 17, the unaffected father of patient 414 had five of these six nucleotide substitutions, except 5741G→A (R1914H), in the homozygous state (figure 5A). Furthermore, arginine at position 1914 is highly conserved among species, whereas glutamine at position 44, valine at position 949, and cysteine at position 1009 were not conserved among species (figure 5B). Among these substitutes, only R1914H substitution was predicted to be possibly damaging by the Polyphen program. None of the 203 Yakut normal controls had the 5741G→A allele in the homozygous state. One hundred Japanese normal controls did not have the 5741G→A allele. Although patient 817 had these nucleotide substitutions in the heterozygous state, we concluded that homozygous 5741G→A substitution in the NBAS gene associates with the SOPH syndrome.


Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M, Nishihira Y, Miyashita A, Fujiwara H, Oyama T, Nogovicina A, Sukhomyasova A, Potapova S, Kuwano R, Takahashi H, Nishizawa M, Onodera O - J. Med. Genet. (2010)

Haplotype of NBAS mutant chromosome and multiple alignment of NBAS (neuroblastoma amplified sequence) protein. (A) Haplotype of NBAS mutant chromosome for family 17 with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) syndrome and chromatograms of the mutation in the NBAS gene. Disease associated haplotype is boxed. Five nucleotide substitutions, 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; and 3026G→C (resulting in the amino acid substitution C1009S) in exon 26 in NBAS, were observed in a patient and her father in the homozygous state. 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 alteration is observed only in the patient. (B) Amino acid sequence alignment of Homo sapiens NBAS (GenBank accession number NP_056993.2) with orthologs from Pan troglodytes (XP_001161679.1), Canis familiaris (XP_540088.2), Gallus gallus (XP_419959.2), and Danio rerio (NP_001038272.1) revealed by the ClustalW program (http://www.ebi.ac.uk/Tools/clustalw/). Conserved amino acid residues are shaded (GeneDoc program, http://www.nrbsc.org/gfx/genedoc/). Each shade represents a degree of conservation (black, 100%; dark grey, 80%; and grey, 60%). The mutated amino acid R1914H was highly conserved from human to fish, whereas Q44E, V949L, and C1009S were less conserved than R1914H. An amino acid homology search was conducted using the standard protein–protein BLAST. An amino acid sequence of human NBAS (GenBank accession number NP_056993.2), chimpanzee NBAS (XP_001161679.1), dog NBAS (XP_540088.2), chicken NBAS (XP_419959.2), and fish NBAS, (NP_001038272.1) were multiply aligned by the ClustalW program, version 1.83 with default parameters.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2921285&req=5

fig5: Haplotype of NBAS mutant chromosome and multiple alignment of NBAS (neuroblastoma amplified sequence) protein. (A) Haplotype of NBAS mutant chromosome for family 17 with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) syndrome and chromatograms of the mutation in the NBAS gene. Disease associated haplotype is boxed. Five nucleotide substitutions, 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; and 3026G→C (resulting in the amino acid substitution C1009S) in exon 26 in NBAS, were observed in a patient and her father in the homozygous state. 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 alteration is observed only in the patient. (B) Amino acid sequence alignment of Homo sapiens NBAS (GenBank accession number NP_056993.2) with orthologs from Pan troglodytes (XP_001161679.1), Canis familiaris (XP_540088.2), Gallus gallus (XP_419959.2), and Danio rerio (NP_001038272.1) revealed by the ClustalW program (http://www.ebi.ac.uk/Tools/clustalw/). Conserved amino acid residues are shaded (GeneDoc program, http://www.nrbsc.org/gfx/genedoc/). Each shade represents a degree of conservation (black, 100%; dark grey, 80%; and grey, 60%). The mutated amino acid R1914H was highly conserved from human to fish, whereas Q44E, V949L, and C1009S were less conserved than R1914H. An amino acid homology search was conducted using the standard protein–protein BLAST. An amino acid sequence of human NBAS (GenBank accession number NP_056993.2), chimpanzee NBAS (XP_001161679.1), dog NBAS (XP_540088.2), chicken NBAS (XP_419959.2), and fish NBAS, (NP_001038272.1) were multiply aligned by the ClustalW program, version 1.83 with default parameters.
Mentions: In the critical region, there were two genes: neuroblastoma-amplified sequence gene (NBAS, MIM 608025) and DEAD (asp-Glu-Ala-Asp) box polypeptide 1 (DDX1) gene (figure 4B). We performed sequence analysis of NBAS and DDX1 in the patients using a series of intronic primers to amplify the coding exons and exon–intronic junctions in the NBAS and DDX1 genes. We found no mutation in DDX1, whereas we identified six nucleotide substitutions in the NBAS gene in the homozygous state in 33 of 34 patients; 130C→G (resulting in the amino acid substitution Q44E) in exon 2; 1611A→G (not altering the amino acid sequence) in exon 16; 2775T→C (not altering the amino acid sequence); 2845G→C (resulting in the amino acid substitution V949L) in exon 25; 3026G→C (resulting in the amino acid substitution C1009S) in exon 26; and 5741G→A (resulting in the amino acid substitution R1914H) in exon 45 (table 2). To exclude the possibility of the presence of heterozygous deletions, we analysed both parents in 10 families and found true homozygosity in all cases. Among these families, in family 17, the unaffected father of patient 414 had five of these six nucleotide substitutions, except 5741G→A (R1914H), in the homozygous state (figure 5A). Furthermore, arginine at position 1914 is highly conserved among species, whereas glutamine at position 44, valine at position 949, and cysteine at position 1009 were not conserved among species (figure 5B). Among these substitutes, only R1914H substitution was predicted to be possibly damaging by the Polyphen program. None of the 203 Yakut normal controls had the 5741G→A allele in the homozygous state. One hundred Japanese normal controls did not have the 5741G→A allele. Although patient 817 had these nucleotide substitutions in the heterozygous state, we concluded that homozygous 5741G→A substitution in the NBAS gene associates with the SOPH syndrome.

Bottom Line: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene.Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state.None of the 203 normal Yakuts individuals had this substitution in the homozygous state.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Yakut Scientific Center of Complex Medical Problems, Siberian Department of Russian Academy of Medical Science, Yakutsk, Russia.

ABSTRACT

Background: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome.

Aims: To identify a causative gene for SOPH syndrome.

Methods: Genomewide homozygosity mapping was conducted in 33 patients in 30 families.

Results: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome.

Conclusion: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

Show MeSH
Related in: MedlinePlus