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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

Immunohistochemical analysis of NBAS (neuroblastoma amplified sequence) protein. (A) Retina of autopsied control subject (58-year-old man) shows expression of an NBAS protein in the cytoplasm of ganglion cells. The scale bar indicates 20 μm. In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells are stained with NBAS antibody (figure 6A), whereas the outer layer cells and an optic nerve are not stained with NBAS antibody (figure 6B). (B) NBAS is not expressed in cerebral optic nerve tract from autopsied control subject (75-year-old woman with myositis). The scale bar indicates 200 μm. (C, D) Cytoplasm of epidermal squamous cells are well stained with an NBAS antibody in a subject with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) (C: 14-year-old boy) and a control (D: 50-year-old woman). The scale bar indicates 50 μm. (E, F) Cytoplasm of neutrophils are well stained with an NBAS antibody in a subject with SOPH (E: 14-year-old boy) and a control (F: 36-year-old man). The scale bar indicates 10 μm. (G, H) Neutrophils are well stained with a LABR antibody both in a subject with SOPH (G: 14-year-old boy) and a control (H: 36-year-old man). The scale bar indicates 5 μm.
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fig6: Immunohistochemical analysis of NBAS (neuroblastoma amplified sequence) protein. (A) Retina of autopsied control subject (58-year-old man) shows expression of an NBAS protein in the cytoplasm of ganglion cells. The scale bar indicates 20 μm. In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells are stained with NBAS antibody (figure 6A), whereas the outer layer cells and an optic nerve are not stained with NBAS antibody (figure 6B). (B) NBAS is not expressed in cerebral optic nerve tract from autopsied control subject (75-year-old woman with myositis). The scale bar indicates 200 μm. (C, D) Cytoplasm of epidermal squamous cells are well stained with an NBAS antibody in a subject with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) (C: 14-year-old boy) and a control (D: 50-year-old woman). The scale bar indicates 50 μm. (E, F) Cytoplasm of neutrophils are well stained with an NBAS antibody in a subject with SOPH (E: 14-year-old boy) and a control (F: 36-year-old man). The scale bar indicates 10 μm. (G, H) Neutrophils are well stained with a LABR antibody both in a subject with SOPH (G: 14-year-old boy) and a control (H: 36-year-old man). The scale bar indicates 5 μm.

Mentions: In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells was stained with NBAS antibody (figure 6A), whereas the outer layer cells and optic nerve were not stained with NBAS antibody (figure 6B). NBAS was also expressed in the cytoplasm of squamous epidermal cells (figure 6C); the expression was comparable between a patient and a control (figure 6C and 6D). With regard to leucocytes, immunostaining for NBAS showed comparable expression in leucocyte cytoplasm of normal individuals and patients with SOPH. The autosomal dominant inherited PHA is caused by heterozygous mutations in the LBR gene.18 Because the amount of LBR quantitatively affects the lobulation of neutrophic nuclei, we investigated expression of the LBR in affected individuals.18 The expression of LBR protein, however, was comparable between normal individuals and patients (figure 6G and H).


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)

Immunohistochemical analysis of NBAS (neuroblastoma amplified sequence) protein. (A) Retina of autopsied control subject (58-year-old man) shows expression of an NBAS protein in the cytoplasm of ganglion cells. The scale bar indicates 20 μm. In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells are stained with NBAS antibody (figure 6A), whereas the outer layer cells and an optic nerve are not stained with NBAS antibody (figure 6B). (B) NBAS is not expressed in cerebral optic nerve tract from autopsied control subject (75-year-old woman with myositis). The scale bar indicates 200 μm. (C, D) Cytoplasm of epidermal squamous cells are well stained with an NBAS antibody in a subject with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) (C: 14-year-old boy) and a control (D: 50-year-old woman). The scale bar indicates 50 μm. (E, F) Cytoplasm of neutrophils are well stained with an NBAS antibody in a subject with SOPH (E: 14-year-old boy) and a control (F: 36-year-old man). The scale bar indicates 10 μm. (G, H) Neutrophils are well stained with a LABR antibody both in a subject with SOPH (G: 14-year-old boy) and a control (H: 36-year-old man). The scale bar indicates 5 μm.
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Related In: Results  -  Collection

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fig6: Immunohistochemical analysis of NBAS (neuroblastoma amplified sequence) protein. (A) Retina of autopsied control subject (58-year-old man) shows expression of an NBAS protein in the cytoplasm of ganglion cells. The scale bar indicates 20 μm. In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells are stained with NBAS antibody (figure 6A), whereas the outer layer cells and an optic nerve are not stained with NBAS antibody (figure 6B). (B) NBAS is not expressed in cerebral optic nerve tract from autopsied control subject (75-year-old woman with myositis). The scale bar indicates 200 μm. (C, D) Cytoplasm of epidermal squamous cells are well stained with an NBAS antibody in a subject with short stature with optic atrophy and Pelger–Huët anomaly (SOPH) (C: 14-year-old boy) and a control (D: 50-year-old woman). The scale bar indicates 50 μm. (E, F) Cytoplasm of neutrophils are well stained with an NBAS antibody in a subject with SOPH (E: 14-year-old boy) and a control (F: 36-year-old man). The scale bar indicates 10 μm. (G, H) Neutrophils are well stained with a LABR antibody both in a subject with SOPH (G: 14-year-old boy) and a control (H: 36-year-old man). The scale bar indicates 5 μm.
Mentions: In the retina, the cytoplasm of retinal ganglia cells and some of the inner layer cells was stained with NBAS antibody (figure 6A), whereas the outer layer cells and optic nerve were not stained with NBAS antibody (figure 6B). NBAS was also expressed in the cytoplasm of squamous epidermal cells (figure 6C); the expression was comparable between a patient and a control (figure 6C and 6D). With regard to leucocytes, immunostaining for NBAS showed comparable expression in leucocyte cytoplasm of normal individuals and patients with SOPH. The autosomal dominant inherited PHA is caused by heterozygous mutations in the LBR gene.18 Because the amount of LBR quantitatively affects the lobulation of neutrophic nuclei, we investigated expression of the LBR in affected individuals.18 The expression of LBR protein, however, was comparable between normal individuals and patients (figure 6G and H).

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