Department of Molecular Genetics, Yakut Scientific Center of Complex Medical Problems, Siberian Department of Russian Academy of Medical Science, Yakutsk, Russia.
J Med Genet. 2010 Aug;47(8):538-48. doi: 10.1136/jmg.2009.074815. Epub 2010 Jun 24.
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.
To identify a causative gene for SOPH syndrome.
Genomewide homozygosity mapping was conducted in 33 patients in 30 families.
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.
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.
遗传性身材矮小综合征是一种临床表现和遗传学均具有异质性的疾病，其病因尚未完全明确。雅库特人是一个生活在亚洲的孤立人群；他们居住在俄罗斯联邦的远东地区，遗传性身材矮小综合征的患病率很高，包括 3-M 综合征。本研究报告了雅库特人中一种新的身材矮小综合征，其特征为常染色体隐性遗传、严重的出生后生长迟缓、具有老年面容的面部畸形、手足小、智力正常、白细胞Pelger-Huët 异常以及伴有视力和色觉丧失的视神经萎缩。这种新的综合征被命名为伴有视神经萎缩和 Pelger-Huët 异常的身材矮小（SOPH）综合征。
确定 SOPH 综合征的致病基因。
对 30 个家系的 33 位患者进行全基因组纯合性作图。
疾病位点定位于染色体 2p24.3 的 1.1 Mb 区域，包括神经母细胞瘤扩增序列（NBAS）基因。随后，34 位患者中的 33 位被确定为 SOPH 综合征，并且在 NBAS 基因中存在纯合的 5741G/A 核苷酸替换（导致氨基酸替换为 R1914H）。203 名正常雅库特人中没有这种纯合替换。免疫组织化学分析显示，NBAS 蛋白在对照组和 SOPH 综合征患者的视网膜神经节细胞、表皮皮肤细胞和白细胞细胞质中均有良好表达。
这些发现提示 NBAS 的功能可能与身材矮小综合征以及视神经萎缩和 Pelger-Huët 异常的发病机制有关。
