Gillespie syndrome - ITPR1 gene

Gillespie syndrome is a process that involves ocular abnormalities, congenital hypotonia, ataxia, and mild to moderate intellectual disability. Eye abnormalities may include iris hypoplasia, partial aniridia, dilated pupils that do not contract in response to light and nystagmus. These eye conditions can cause decreased visual acuity and photophobia. On the other hand, the problems of balance and movement are due to hypoplasia of the cerebellum, which can lead to hypotonia and delay in the development of motor skills and language. Other features of Gillespie syndrome may include abnormalities of the vertebrae and malformations of the heart.

This process is due to mutations in the ITPR1 gene (inositol 1,4,5-trisphosphate receptor type 1), located on the short arm of chromosome 3 (3p26.1), which encodes a protein that is part of a channel (ITPR1) that controls the flow of calcium ions inside the cells. In response to certain signals, the ITPR1 channel releases calcium ions stored in the endoplasmic reticulum in the cytoplasm. Proper regulation of the concentration of calcium ions inside cells is important for the development and function of various tissues and organs.

At least 13 mutations of the ITPR1 gene have been described in people with Gillespie syndrome. It is likely that the mutations described give rise to a protein with an altered structure. Homotetrameters of calcium channels constituted with altered proteins are believed to be unstable. Although the deficiency of normal ITPR1 channels affects the ability of the cell to regulate the concentration of calcium ions, the specific connection between these changes and the signs and symptoms of Gillespie syndrome is unknown. 

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. In some cases, the process is inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. Some affected individuals inherit the mutation of an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of the disease in their family. It is believed that autosomal dominant cases of Gillespie syndrome arise from a dominant negative effect, which means that the altered protein encoded from one copy of the gene interferes with the function of the normal protein produced from the other copy of the gene.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Gillespie syndrome, by means of the complete PCR amplification of the exons of the ITPR1 gene, and their subsequent sequencing.

Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).