Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function

Rechtzigel, Mitchell J.; Meyerink, Brandon; Leppert, Hannah; Johnson, Tyler B.; Cain, Jacob T.; Ferrandino, Gavin; May, Danielle G.; Roux, Kyle J.; Brudvig, Jon; Weimer, Jill M.

doi:10.1101/2021.09.16.460691

2021

DOI: 10.1101/2021.09.16.460691

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Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function

Mitchell J. Rechtzigel

Brandon Meyerink

Hannah Leppert

et al.

Abstract: Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e. SNAREs and tethers) and aberrant synaptic SNARE dynamics in vivo, demonstrating a nove… Show more

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Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Rus

Weissensteiner

Pereira

et al. 2022

Orphanet J Rare Dis

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Background Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

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Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Rus

Weissensteiner

Pereira

et al. 2022

Orphanet J Rare Dis

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Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function

Cited by 1 publication

References 22 publications

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

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