Kallabi Fakhri, Belghuith Neila, Aloulou Hajer, Kammoun Thouraya, Ghorbel Soufiane, Hajji Mouna, Gallas Syrine, Chemli Jaleleddine, Chabchoub Imen, Azzouz Hatem, Ben Chehida Amel, Sfaihi Lamia, Makni Saloua, Amouri Ali, Keskes Leila, Tebib Neji, Ben Becher Saayda, Hachicha Monjia, Kamoun Hassen
Laboratory of Human Molecular Genetics, Faculty of Medicine, Sfax, Tunisia.
Department of Medical Genetics, C.H.U. Hedi Chaker, Sfax, Tunisia.
Arch Med Res. 2016 Feb;47(2):105-10. doi: 10.1016/j.arcmed.2016.04.004. Epub 2016 Apr 28.
Allgrove syndrome is characterized by achalasia, alacrima, and adrenal insufficiency as well as being associated with progressive neurological signs. This is an autosomal recessive disorder due to mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes a protein of 546 amino acids, ALADIN. Mutations in this genwere reported in families from North Africa and Europe. Our objective is to conduct a clinical, molecular and genetic study of 26 Tunisian patients with Allgrove syndrome.
We report 26 Tunisian patients with between two and four clinical features associated with Allgrove syndrome. Blood samples were collected and isolated DNA derived from subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR and sequencing. PCR-RFLP method was performed to identify the frequent mutations found.
Sequencing of the AAAS gene revealed a major homozygous mutation (c.1331+1G>A) in 25 patients and R286X mutation in one patient. The presence of a major mutation in several unrelated affected individuals suggests the presence of a founder effect in Tunisia and allows for a fast and targeted molecular diagnosis.
We created an easy and rapid molecular enzymatic protocol based on PCR-RFLP using MvaI restriction enzyme that directly targets this major mutation and can be used for prenatal diagnosis and genetic counseling for Tunisian families at risk. To the best of our knowledge, this is the first major series report of Allgrove syndrome in Tunisia.
奥尔格罗夫综合征的特征为贲门失弛缓症、无泪症和肾上腺功能不全，还伴有进行性神经体征。这是一种常染色体隐性疾病，由位于12q13染色体上的AAAS基因突变所致。AAAS基因编码一种含546个氨基酸的蛋白质，即ALADIN。在来自北非和欧洲的家族中报道了该基因的突变。我们的目标是对26例突尼斯奥尔格罗夫综合征患者进行临床、分子和遗传学研究。
我们报告了26例具有两到四种与奥尔格罗夫综合征相关临床特征的突尼斯患者。采集血样，提取受试者的DNA并进行扩增。通过聚合酶链反应（PCR）和测序分析AAAS基因的完整序列。采用PCR-限制性片段长度多态性（RFLP）方法鉴定所发现的常见突变。
AAAS基因测序显示，25例患者存在一个主要的纯合突变（c.1331+1G>A），1例患者存在R286X突变。在几个无亲缘关系的受影响个体中存在主要突变，这表明突尼斯存在奠基者效应，有助于进行快速且有针对性的分子诊断。
我们基于使用MvaI限制性内切酶的PCR-RFLP创建了一种简便快速的分子酶学方法，该方法直接针对这一主要突变，可用于对有风险的突尼斯家庭进行产前诊断和遗传咨询。据我们所知，这是突尼斯关于奥尔格罗夫综合征的首个主要系列报告。
