Mole Laboratory: Adult Batten Disease

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Mole Laboratory:Mole Laboratory:
Adult Batten DiseaseAdult Batten Disease
Sara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Charlotte Ridler, Varun Warrier, Rachel BrownSara Mole, Michael Bond, Mariana Vieira, Davide Marotta, Sophia kleine Holthaus, Charlotte Ridler, Varun Warrier, Rachel Brown
MRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.ukMRC Laboratory for Molecular Cell Biology, University College London, London, UK, WC1E 6BT, s.mole@ucl.ac.uk
INTRODUCTION
(Laboratory Objectives)
 The cause of most cases of
adult onset NCL until recently has
not been known.
We have been collecting cases
(DNA and cell lines) for many
years and built up a large
resource of adult onset NCL
(recessive and dominant).
We have been analysing these
cases for mild mutations in genes
that normally cause childhood
onset NCL. Mutations in several
childhood NCL genes can cause
adult NCL.
In families that appear to have
disease caused by mutations in
novel genes we are using the
powerful new DNA sequencing
technologies to identify new
genes.
4
Key Projects What this means
For Therapy
9
Diagnostic algorithms guide gene
testing and help to reach a genetic
diagnosis
Summary table of NCL genes with adult
onset cases highlighted. Some are new
genes that have been identified
collaboratively using the outlined strategy
Acknowledgements:
1. It is very hard to develop a
new therapy for a disease
where the cause is not
known.
2. Identifying the genes
causing disease in such
families is the first step.
3. Once a gene is identified,
what it does normally, and
what is going wrong in the
disease can be studied.
4. This information will help in
the development of
targeted therapy.
5. There are not many
families with adult Batten
disease. We therefore
collaborate with other
laboratories around the
world to identify these
genes.
6. We also use the same
approach for any family
with Batten disease that is
not genetically defined.
Function
Therapy
Mutations
Disease
Genes
Models
Gene
symbol
Protein Diseases
Soluble lysosomal
enzyme deficiencies
CTSD
CLN10
Cathepsin D CLN10 disease, congenital
CLN10 disease, late infantile
CLN10 disease, juvenile
CLN10 disease, adult
PPT1
CLN1
Palmitoyl protein thioesterase
1, PPT1
CLN1 disease, infantile
CLN1 disease, late infantile
CLN1 disease, juvenile
CLN1 disease, adult
TPP1
CLN2
Tripeptidyl peptidase 1, TPP1 CLN2 disease, late infantile
CLN2 disease, juvenile
CTSF
CLN13
Cathepsin F CLN13 disease, adult Kufs type B
Non-enzyme
deficiencies,
(functionsof
identified proteins
generally poorly
understood at the
current time)
CLN3 Transmembrane protein CLN3 disease, juvenile
CLN5 Soluble; lysosomal CLN5 disease, late infantile
CLN5 disease, juvenile
CLN5 disease, adult
CLN6 Transmembrane protein; ER CLN6 disease, late infantile
CLN6 disease, adult Kufs type A
MFSD8
CLN7
Major facilitator superfamily
domain-containing protein 8
Transmembrane protein;
Endolysosomal transporter
CLN7 disease, late infantile
CLN8 Transmembrane protein; ER,
ER-Golgi intermediate
complex
CLN8 disease, late infantile
CLN8 disease, EPMR
DNAJC5
CLN4
Soluble cysteine string protein
α
CLN4 disease, adult autosomal
dominant
GRN
CLN11
Progranulin CLN11 disease, adult
Heterozygous mutations cause
frontotemporal lobar dementia
ATP13A2
CLN12
P-type ATPase CLN12 disease, juvenile
Mutations also cause Kufor-Rakeb
syndrome
KCTD7
CLN14
Potassium channel
tetramerization domain-
containing protein 7
CLN14 disease, infantile
Mutation also causes progressive
myoclonic epilepsy-3
Others: those whose
classification is
uncertain because of
incomplete
diagnostic
investigationsor
absence of
confirmed
gene/mutation
designation, or
where NCLisa rare
or minor mutation-
specificphenotype
? Mutations not yet defined in
any gene
Congenital/infantile variants
? Mutations not yet defined in
any gene
Late infantile variants
?CLN9? Mutations not yet defined in
any gene
Juvenile variants
? Mutations not yet defined in
any gene
Late onset/adult variants including
some adult Kufs type B
CLCN6 Mutations not yet found on
both disease alleles in human
disease
Chloride transport defect, adult
onset
SGSH Mutations usually cause
MPSIIIA
Adult onset
Family
Sample Database
Clinical details; EM Pathology, Lymphocyte vacuoles;
Enzyme results; Sequencing analysis
Diagnosis of NCL suspected
Sequence known
NCL genes
NCL Enzyme tests
New gene identification
Linkage, exome sequencing
CLN1, CLN2 or CLN10 disease
CLN1, CLN2 or CLN10
mutations
CLN3, CLN5, CLN6, CLN7, CLN8
mutations
Mutation analysis of CLN?
in existing cohorts
Schema of approach to identify
new genes