Travaglini Lorena, Brancati Francesco, Attie-Bitach Tania, Audollent Sophie, Bertini Enrico, Kaplan Josseline, Perrault Isabelle, Iannicelli Miriam, Mancuso Brunella, Rigoli Luciana, Rozet Jean-Michel, Swistun Dominika, Tolentino Jerlyn, Dallapiccola Bruno, Gleeson Joseph G, Valente Enza Maria, Zankl A, Leventer R, Grattan-Smith P, Janecke A, D'Hooghe M, Sznajer Y, Van Coster R, Demerleir L, Dias K, Moco C, Moreira A, Kim C Ae, Maegawa G, Petkovic D, Abdel-Salam G M H, Abdel-Aleem A, Zaki M S, Marti I, Quijano-Roy S, Sigaudy S, de Lonlay P, Romano S, Touraine R, Koenig M, Lagier-Tourenne C, Messer J, Collignon P, Wolf N, Philippi H, Kitsiou Tzeli S, Halldorsson S, Johannsdottir J, Ludvigsson P, Phadke S R, Udani V, Stuart B, Magee A, Lev D, Michelson M, Ben-Zeev B, Fischetto R, Benedicenti F, Stanzial F, Borgatti R, Accorsi P, Battaglia S, Fazzi E, Giordano L, Pinelli L, Boccone L, Bigoni S, Ferlini A, Donati M A, Caridi G, Divizia M T, Faravelli F, Ghiggeri G, Pessagno A, Briguglio M, Briuglia S, Salpietro C D, Tortorella G, Adami A, Castorina P, Lalatta F, Marra G, Riva D, Scelsa B, Spaccini L, Uziel G, Del Giudice E, Laverda A M, Ludwig K, Permunian A, Suppiej A, Signorini S, Uggetti C, Battini R, Di Giacomo M, Cilio M R, Di Sabato M L, Leuzzi V, Parisi P, Pollazzon M, Silengo M, De Vescovi R, Greco D, Romano C, Cazzagon M, Simonati A, Al-Tawari A A, Bastaki L, Mégarbané A, Sabolic Avramovska V, de Jong M M, Stromme P, Koul R, Rajab A, Azam M, Barbot C, Martorell Sampol L, Rodriguez B, Pascual-Castroviejo I, Teber S, Anlar B, Comu S, Karaca E, Kayserili H, Yüksel A, Akcakus M, Al Gazali L, Sztriha L, Nicholl D, Woods C G, Bennett C, Hurst J, Sheridan E, Barnicoat A, Hennekam R, Lees M, Blair E, Bernes S, Sanchez H, Clark A E, DeMarco E, Donahue C, Sherr E, Hahn J, Sanger T D, Gallager T E, Dobyns W B, Daugherty C, Krishnamoorthy K S, Sarco D, Walsh C A, McKanna T, Milisa J, Chung W K, De Vivo D C, Raynes H, Schubert R, Seward A, Brooks D G, Goldstein A, Caldwell J, Finsecke E, Maria B L, Holden K, Cruse R P, Swoboda K J, Viskochil D
CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy.
Am J Med Genet A. 2009 Oct;149A(10):2173-80. doi: 10.1002/ajmg.a.33025.
Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
纤毛病是一类不断扩大的罕见疾病，其特征是多器官受累，由编码初级纤毛或其附属器蛋白的基因突变引起。在这些基因中，CEP290具有有趣的等位基因谱，在Joubert综合征及相关疾病（JSRD）、Meckel综合征（MKS）、Senior-Loken综合征和孤立性Leber先天性黑蒙（LCA）中常见突变。尽管这些疾病是隐性遗传，但在一部分患者中只能检测到一个CEP290突变。为了评估涉及CEP290基因的基因组重排是否可能是这些病例中的一种突变机制，我们对两组CEP290杂合患者进行了基因组DNA的外显子剂量分析，分别包括5例JSRD/MKS病例和4例LCA。在1例JSRD患者中，我们鉴定出一个包含CEP290 C末端的大的杂合缺失，导致mRNA表达明显降低。在其余先证者中未发现拷贝数改变。本研究扩展了CEP290基因型谱，将多外显子缺失纳入其中。尽管这种机制似乎并不常见，但对于仅鉴定出一个CEP290突变等位基因的患者，应考虑筛查基因组重排。
