title: Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease).
abstract: Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl-peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl-peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype-phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.
authors: Center for Human and Clinical Genetics, Leiden University Medical Center, The Netherlands.
authors: Yu
authors: Y
authors: Sun
authors: Rowida
authors: R
authors: Almomani
authors: Guido J
authors: GJ
authors: Breedveld
authors: Gijs W E
authors: GW
authors: Santen
authors: Emmelien
authors: E
authors: Aten
authors: Dirk J
authors: DJ
authors: Lefeber
authors: Jorrit I
authors: JI
authors: Hoff
authors: Esther
authors: E
authors: Brusse
authors: Frans W
authors: FW
authors: Verheijen
authors: Rob M
authors: RM
authors: Verdijk
authors: Marjolein
authors: M
authors: Kriek
authors: Ben
authors: B
authors: Oostra
authors: Martijn H
authors: MH
authors: Breuning
authors: Monique
authors: M
authors: Losekoot
authors: Johan T
authors: JT
authors: den Dunnen
authors: Bart P
authors: BP
authors: van de Warrenburg
authors: Anneke J A
authors: AJ
authors: Maat-Kievit
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D008969:Molecular Sequence Data; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012313:RNA / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D012313:RNA; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human