Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations
Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations
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DOI：
10.1111/j.1399-0004.2011.01734.x
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Ali, B. R.
中科院分区：
文献类型：
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作者：
Akawi, N. A.;Al-Gazali, L.;Ali, B. R.
Akawi NA, Al-Gazali L, Ali BR。UAE纤维软骨形成患者的临床和分子分析扩大了表型并揭示了两个COL11A1纯合零突变。纤维软骨形成是一种以短肢骨骼发育不良为特征的新生儿致死性罕见隐性遗传疾病。在这里，我们报告两名患者从两个不相关的近亲阿联酋家庭谁出人意料地幸存到3岁和6岁。这些患者表现出其他症状，包括发育迟缓、深度感觉神经性耳聋、严重近视和进行性严重骨骼异常。利用纯合子作图证实了thompson等人在2010年的最新发现，阿联酋家族的纤维软骨形成与1号染色体有关联。筛选COL11A1基因发现两个零纯合突变[c]。4084C b> T （p.R1362X）和c.3708+437T b> G]。c.4084C>T突变预计在Arg1362位置引入一个停止密码子，而c.3708+437T>G突变导致48和49外显子之间的内含子假外显子激活。这导致在mRNA中插入50个核苷酸。这些突变的携带者表现为视力缺陷，听力正常。总之，我们的数据将提高对纤维软骨形成的整体理解，特别是在存活的纯合子患者中，至少部分地解释了与COL11A1基因突变相关的表型变异。
Akawi NA, Al-Gazali L, Ali BR. Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations. Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensoryneural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.