Valente Enza Maria, Brancati Francesco, Silhavy Jennifer L, Castori Marco, Marsh Sarah E, Barrano Giuseppe, Bertini Enrico, Boltshauser Eugen, Zaki Maha S, Abdel-Aleem Alice, Abdel-Salam Ghada M H, Bellacchio Emanuele, Battini Roberta, Cruse Robert P, Dobyns William B, Krishnamoorthy Kalpathy S, Lagier-Tourenne Clotilde, Magee Alex, Pascual-Castroviejo Ignacio, Salpietro Carmelo D, Sarco Dean, Dallapiccola Bruno, Gleeson Joseph G
Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy.
Ann Neurol. 2006 Mar;59(3):527-34. doi: 10.1002/ana.20749.
Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown.
We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign.
We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity.
AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.
乔伯特综合征（JS）是一种隐性遗传的发育性脑疾病，已确定了多个致病染色体位点。其特征为小脑蚓部发育不全以及一种特殊的中脑-后脑“磨牙”征，这一表现也见于一组与乔伯特综合征相关的疾病（JSRD），且具有广泛的表型变异性。首个通过定位克隆得到的基因AHI1的突变频率尚不清楚。
我们在137个患有JSRD且经影像学证实有磨牙征的家系中筛查AHI1基因的突变情况。
我们在10个患有单纯JS或JS合并视网膜及/或其他中枢神经系统异常的家系中鉴定出15个有害突变。未在包括肾脏或肝脏受累的JSRD家系中检测到突变。在大多数无近亲结婚史的家系中鉴定出了反式杂合突变。大多数突变是截短突变或剪接错误，仅在高度保守的WD40重复结构域中有一个错义突变，该突变导致了严重程度相似的疾病。
AHI1突变是特定形式JSRD患者疾病的常见病因。
