A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.

Klar, Joakim,1974-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi (author)

Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.

Ali, ZafarUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi,PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan(Swepub:uu)zafal581 (author)
Farooq, MuhammadPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Khan, KamalPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Wikström, JohanUppsala universitet,Radiologi(Swepub:uu)jwi06759 (author)
Iqbal, MariaPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Zulfiqar, ShumailaPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Faryal, SanamPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Baig, Shahid MahmoodPIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan (author)
Dahl, NiklasUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi(Swepub:uu)nikldahl (author)
Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

In:European Journal of Human Genetics: Springer Science and Business Media LLC25:7, s. 848-8531018-48131476-5438

By the author/editor: Klar, Joakim, 19 ...; Ali, Zafar; Farooq, Muhammad; Khan, Kamal; Wikström, Johan; Iqbal, Maria; show more...; Zulfiqar, Shumai ...; Faryal, Sanam; Baig, Shahid Mah ...; Dahl, Niklas; show less...

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