Identification and characterization of genes in patients with severe mental retardation caused by autosomal dominant trait.

常染色体显性遗传性重度智力低下患者基因的鉴定和特征分析。

• 批准号: 13670158
• 负责人: WAKAMATSU Nobuaki
• 金额: $ 2.3万
• 依托单位: Institute for Developmental Research, Aichi Human Service Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670158/
• 关键词: mental retardation; autosomal dominant; translocation; ZFHX1B; SIP1; microcephaly; facial dysmorphism; congenital heart disease; agenesis of corpus callosum; nonsense mutation; frame shift mutation; 神経呈; 脳発達障害

Mental retardation (MR) is the most common cause of serious handicap in children and young adults. Defining features of MR include an IQ (intelligence quotient) of less than 70, together with associated functional deficits in adaptive behavior, which manifest themselves before 18 years of age. The molecular mechanisms underlying MR are quite heterogeneous and most of the genes responsible for MR are still unidentified. We have adopted the strategy of determining the chromosomal translocation breakpoints in two patients with profound mental retardation. Genes located at the translocation breakpoints should be candidates for MR and these conditions are likely caused by autosomal dominant traits. One patient (case 1 ) has a chromosomal translocation between 2q22 and 13q22 and the other (case 2) has 6q16 and 12p12. Case 1 has profound mental retardation, facial dysmorphism, microcephaly, delayed motor development, congenital heart disease and Hirschsprung disease, and was diagnosed as suffering from the Hirschsprung disease-Mental retardation (HSCR-MR) syndrome. The other patient has profound mental retardation and delayed motor development. We have identified ZFHX1B gene as a cause of the HSCR-MR syndrome, located at the 2q22 breakpoint. We also determined a translocation breakpoint on 6q16 from case 2. However our results suggest that the MR of case 2 is likely due to a defect in a gene located at 12p12.

智力低下（MR）是儿童和年轻人严重障碍的最常见原因。 MR的定义特征包括少于70的智商（智能商），以及适应性行为的相关功能缺陷，在18岁之前表现出自己。 MR的分子机制是非常异构的，大多数负责MR的基因仍然不明。我们采用了确定两名智力低下患者的染色体易位断点的策略。位于易位断点的基因应该是MR的候选物，这些条件可能是由常染色体显性性状引起的。一名患者（病例1）的染色体易位在2q22和13q22之间，另一名患者（案例2）的6q16和12p12。病例1具有深刻的智力低下，面部畸形，小头畸形，运动延迟的运动发育，先天性心脏病和赫希斯普伦病，并被诊断为患有Hirschsprung疾病迟缓（HSCR-MR）综合征。另一名患者的智力低下并延迟了运动的发展。我们已经将ZFHX1B基因确定为位于2q22断点的HSCR-MR综合征的原因。我们还从案例2中确定了2016年第6季度的易位断点。但是，我们的结果表明，情况2的MR可能是由于位于12p12的基因中的缺陷所致。

项目成果

Yamada K^*, Yamada Y^*, Nomura N, et al.(計16名): "Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features"Am J Hum Genet. 69. 1178-1185 (2001)

Yamada K^*、Yamada Y^*、Nomura N 等人（总共 16 人）：“编码 Smad 相互作用蛋白 1 的 ZFHX1B 中的无义突变和移码突变会导致具有多种临床特征的复杂发育障碍。 《Am J Hum Genet》。69. 1178-1185 (2001)

Yamada K, et al.: "Molecular analysis of Japanese patients with Rett syndrome : Identification of fire novel mutations and genotype-phenotypecarrelation"Hum Mutat. 18(3). 253-Online #443 (2001)

Yamada K 等人：“日本 Rett 综合征患者的分子分析：火新突变的鉴定和基因型-表型相关性”Hum Mutat。

Wakamatsu N, et al.: "Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease"Nature Genet. 27(4). 369-270 (2001)

Wakamatsu N 等人：“编码 Smad 相互作用蛋白 1 的 SIP1 突变导致先天性巨结肠症”Nature Genet。

Yamada K, et al.: "A rare case of complete human eryhrocyte AMP deaminase deficiency due to two novel missorse mutations in AMPD3"Hum Mutat. 17(1). 78-Online #395 (2000)

Yamada K 等人：“由于 AMPD3 中两个新的错配突变而导致人类红细胞 AMP 脱氨酶完全缺乏的罕见病例”Hum Mutat。

Yoneda M, Fujita T, Yamada Y, Yamada K, Fujii A, Inagaki T, Nakagawa H, Shimada A, Kishikawa M, Nagaya M, Azuma T, Kuriyama M, Wakamatsu N: "Late infantile Hirschsprung disease-mental retardation syndrome with a 3-bp deletion in ZFHX1B"Neurology. 59(10).

Yoneda M、Fujita T、Yamada Y、Yamada K、Fujii A、Inagaki T、Nakakawa H、Shimada A、Kishikawa M、Nagaya M、Azuma T、Kuriyama M、Wakamatsu N：“晚期婴儿先天性巨结肠症-智力低下综合征