Dentici Maria Lisa, Barresi Sabina, Nardella Marta, Bellacchio Emanuele, Alfieri Paolo, Bruselles Alessandro, Pantaleoni Francesca, Danieli Alberto, Iarossi Giancarlo, Cappa Marco, Bertini Enrico, Tartaglia Marco, Zanni Ginevra
Medical Genetics, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Molecular Genetics and Functional Genomics, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Gene. 2017 Sep 10;628:141-145. doi: 10.1016/j.gene.2017.07.017. Epub 2017 Jul 8.
ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespie syndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia. We performed next generation sequencing in two simplex families with Gillespie syndrome and identified de novo pathological mutations localized in the C-terminal channel domain of ITPR1 in both patients: a recurrent deletion (p.Lys2596del) and a novel missense mutation (p.Asn2576Ile) close to a point of constriction in the Ca pore. Our study expands the mutational spectrum of ITPR1 and confirms that ITPR1 screening should be implemented in patients with congenital cerebellar ataxia with or without iris hypoplasia.
ITPR1编码一种肌醇1,4,5-三磷酸（InsP3）的细胞内受体，该受体在小脑中高度表达，并参与钙稳态的调节。ITPR1的InsP3结合结构域（IRBIT）中的错义突变常与早发性小脑萎缩相关。吉莱斯皮综合征的特征是先天性共济失调、轻度至中度智力残疾和虹膜发育不全。显性或隐性ITPR1突变最近与这种综合征性共济失调形式相关。我们对两个患有吉莱斯皮综合征的单基因家族进行了二代测序，并在两名患者中均鉴定出位于ITPR1 C端通道结构域的新生病理性突变：一个复发性缺失（p.Lys2596del）和一个靠近钙孔收缩点的新型错义突变（p.Asn2576Ile）。我们的研究扩展了ITPR1的突变谱，并证实对于有或没有虹膜发育不全先天性小脑共济失调患者均应进行ITPR1筛查。
