Hypomyelination and developmental delay associated with VPS11

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New loci
ORIGINAL ARTICLE
Hypomyelination and developmental delay
associated with VPS11 mutation in Ashkenazi-Jewish
patients
Shimon Edvardson,1 Frank Gerhard,2 Chaim Jalas,3 Jens Lachmann,2 Dafna Golan,4
Ann Saada,1 Avraham Shaag,1 Christian Ungermann,2 Orly Elpeleg1
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
jmedgenet-2015-103239).
1
Monique and Jacques Roboh
Department of Genetic
Research, Hadassah-Hebrew
University Medical Center,
Jerusalem, Israel
2
Department of Biology/
Chemistry, Biochemistry
Section, University of
Osnabrück, Osnabrück,
Germany
3
Bonei Olam, Center for Rare
Jewish Genetic Disorders,
Brooklyn, New York, USA
4
Maccabi Health Services,
Child Development Center,
Jerusalem, Israel
Correspondence to
Professor Orly Elpeleg,
Monique and Jacques Roboh
Department of Genetic
Research, Hadassah-Hebrew
University Medical Center,
Jerusalem 91120, Israel;
Elpeleg@hadassah.org.il
Dr. Christian Ungermann,
Department of Biology/
Chemistry, Biochemistry
Section, University of
Osnabrück, Osnabrück,
Germany
SE, FG and CJ contributed
equally.
Received 2 May 2015
Revised 9 July 2015
Accepted 3 August 2015
ABSTRACT
Background The genetic heterogeneity of
developmental delay and cognitive impairment is vast.
The endocytic network is essential for neural development
and synaptic plasticity by regulating the sorting of
numerous transmembrane proteins. Disruption of the
pathway can lead to neuronal pathology. Endosomal
biogenesis relies on two Rab proteins, Rab5 and Rab7,
which bind to two hexameric tethering complexes, the
endosomal class C core vacuole/endosome tethering
complex (CORVET) and the late endosomal/lysosomal
homotypic fusion and protein sorting complex (HOPS).
Both complexes consist of four core proteins and differ by
their specific Rab-binding proteins.
Objectives To identify the molecular basis of a
neurological disease, which consists of global
developmental stagnation at 3–8 months, increasing
appendicular spasticity, truncal hypotonia and acquired
microcephaly, with variable seizure disorder, accompanied
by thin corpus callosum, paucity of white matter and
delayed myelination in eight patients from four unrelated
Ashkenazi-Jewish (AJ) families.
Methods Exome analysis, homozygosity mapping and
Mup1-GFP transport assay in mutant yeast.
Results Homozygosity for a missense mutation,
p.Cys846Gly, in one of the endosomal biogenesis core
proteins, VPS11, was identified in all the patients. This
was shown to be a founder mutation with a carrier
frequency of 0.6% in the AJ population. The homologous
yeast mutant had moderate impairment
of fusion of the late endosome to the vacuole in
Mup1-GFP transport assay.
Conclusions We speculate that in neuronal cells,
impairment of fusion of the late endosome to the vacuole
would attenuate the degradation of plasma membrane
receptors, thereby underlying the progressive neuronal
phenotype in our patients. The VPS11
p.Cys846Gly mutation should be added to the AJ carrier
screening panel.
INTRODUCTION
To cite: Edvardson S,
Gerhard F, Jalas C, et al. J
Med Genet Published Online
First: [ please include Day
Month Year] doi:10.1136/
jmedgenet-2015-103239
Neural development and the synaptic plasticity
required for cognitive development necessitates the
dynamic and local remodelling of the protein and
lipid content of the neuronal cell surface, including
millions of highly specialised synaptic connections.1
Central to controlling the composition of the cell
surface is the endocytic network.2 Here, the specific internalisation of transmembrane proteins is
balanced by the selective sorting of the internalised
proteins and lipids back to the cell surface or to the
lysosome for downregulation and degradation. By
regulating the sorting of numerous transmembrane
proteins, including cell adhesion molecules, signalling receptors and ion channels, the endocytic
network regulates the structural and functional
remodelling of synapses.1
The endocytic network relies on two Rab proteins for endosomal biogenesis—Rab5, which is
required for early endosome fusion, and Rab7,
which acts in the fusion of the mature late endosome with the lysosome.2–4 During endosomal maturation, Rab5 and Rab7 bind to two hexameric
tethering complexes, the endosomal CORVET
(‘class C core vacuole/endosome tethering’) and the
late endosomal/lysosomal HOPS (‘homotypic
fusion and protein sorting’) complex5–11 (figure 1).
In metazoans, CORVET functions in endosome–
endosome fusion by binding to Rab5, whereas, at
least in yeast, HOPS promotes fusion by interacting
with the Rab7-homolog Ypt7.12 13 Both CORVET
and HOPS consist of four core proteins (collectively named C-proteins), Vps11, Vps16, Vps18 and
Vps33, and differ by the Rab5-binding Vps3 and
Vps8 in CORVET or Rab7/Ypt7-binding Vps39 and
Vps41 in HOPS (figure 1).
We now report on patients with hypomyelination
and developmental delay associated with a defect in
the C-protein Vps11.
CASE REPORTS
The subjects of this study were eight children from
four unrelated Ashkenazi-Jewish (AJ) families
(figure 2A) currently 13 months to 21 years old.
All affected children were from normal pregnancies and deliveries with head circumference at birth
between +1 and −1 SD. The patients presented
with global developmental stagnation between 3
and 8 months of age. Subsequent course was characterised by increasing appendicular spasticity up to
grade 3 at Ashworth scale with resultant contractures, truncal hypotonia, which required the use of
corset for stabilisation and acquired microcephaly
with head circumference eventually at around −2
to −3 SD; however, the youngest patient (C-II-1)
did not have microcephaly or descent in percentiles
of head circumference at 13 months of age. Peak
developmental milestones consisted of independent
sitting and 2–3 words of expressive language in
two children. No syndromic stigmata were present,
and review of systems including clinical immune
Edvardson S, et al. J Med Genet 2015;0:1–5. doi:10.1136/jmedgenet-2015-103239
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1
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New loci
Figure 1 The endosomal–lysosomal
network as characterized in yeast. The
fate of a receptor-bound ligand that
enters the endocytic pathway until its
degradation in the lysosome/vacuole
lumen is shown. Endocytic vesicles are
tethered to early endosomes. The
CORVET complex functions in
endosome–endosome fusion by binding
to the small GTPase Rab5. At the late
endosome (also called Multivesicular
body, MVB), Rab5 is replaced by Rab7,
which then interacts with homotypic
fusion and protein sorting (HOPS) to
promote fusion. The arrangement of
HOPS and CORVET subunits is shown in
the box; HOPS is also required for
homotypic vacuole–vacuole (or
lysosome) fusion and for fusion of
autophagosomes with the vacuole/
lysosome. Golgi-derived adapter
protein complex 3 (AP-3) vesicles
(shown here with a cargo in blue) fuse
directly in a HOPS-dependent manner
with the yeast vacuole. Reprinted with
permission from Ref. 17
function has not shown involvement of other organs. No cutaneous or ocular findings were present except in patient C-II-1
who was noted to have subalbinotic retinae. In three children,
seizures were noted; however, these were rare, consisted of
complex partial seizures from 4–6 months of age, and were
easily controlled with antiepileptic medications. Brain MRI disclosed a fairly consistent pattern of thin corpus callosum and
paucity of white matter with a normal sequence of myelination,
but with delayed onset and rate (figure 3), meeting the definition of hypomyelinating leukodystrophy.14 The most advanced
MRI performed at 17 years in patient S-II-2 disclosed cerebellar
atrophy as well. The salient features of the patients are summarised in table 1. Exome analysis was opted after routine diagnostic investigations were negative.
METHODS
Whole exome analysis
Exonic sequences were enriched in the DNA samples of patient
Z-II-1, B-II-1 and C-II-1 using SureSelect Human All Exon 50
Mb Kit (Agilent Technologies, Santa Clara, California, USA).
Sequences were determined by HiSeq2000 (Illumina, San Diego,
California, USA), and 100 bp were read paired end. Reads alignment and variant calling were performed with DNAnexus software (Palo Alto, California, USA) using the default parameters
with the human genome assembly hg19 (GRCh37) as a reference. Parental consent was given for DNA studies. The study was
performed with the approval of the ethical committees of
Hadassah Medical Center and the Ministry of Health. Carrier
rate was determined using the variants list of the exome analyses
of 3232 unrelated anonymous American AJ.
Yeast strains and plasmids
Genetically modified yeast Saccharomyces cerevisiae was made
by homologous recombination of PCR-amplified cassettes. The
generated yeast strains are listed in the online supplementary
table S1. Vps11 and Vps11 mutant genes were introduced to
pRS416 plasmids under the control of the NOP1 promoter for
transformation into the vps11Δ background strain. Cells were
Figure 2 (A) Families’ pedigree and
genotype of the p.C846G mutation in
the VPS11 gene. (B) The p.C846G
mutation (asterisk) in a healthy control
(upper lane), an obligatory
heterozygous (middle lane) and a
patient (lower lane). (C) Conservation
of cys846 (asterisk) throughout
evolution and among members of the
human VPS protein family.
2
Edvardson S, et al. J Med Genet 2015;0:1–5. doi:10.1136/jmedgenet-2015-103239
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New loci
After incubation at specific temperatures, the cells were pelleted,
resuspended in 20 mL media and subjected to microscopy.
Quantification
Quantification was performed with FijiImageJ16 and the Cell
Counter plugin (developed by Kurt de Vos, University of
Sheffield, Academic Neurology). Cells of vps11Δ Mup1-GFP
VPS11 (wild type) and vps11Δ Mup1-GFP VPS11 C952G
(mutant) both grown at 37°C and with the addition of methionine were counted. The cells were divided into two groups.
RESULTS
Figure 3 Brain MRI of patient S-II-2 at 17 years showing thin corpus
callosum (arrow in A), paucity of white matter with increased T2 signal
on the remaining periventricular white matter (arrow in B) and vermis
atrophy (dashed arrow in A).
grown in synthetic medium supplemented with amino acids and
2% glucose at 26°C for 16–20 h to logarithmic phase and an
OD600 of 0.6–0.8. Afterwards, the cells were split, washed and
resuspended in the medium to an OD600 of 0.2 and further
grown for 3–5 h at 26°C. The cultures were then stained with
FM4-64 as subsequently described, and pictures were taken.
Fluorescence microscopy
The vacuolar membrane was stained with 30 μM FM4-64 for
30 min ( pulse). Washing with dye-free SDC-URA (Synthetic
dextrose complex without uracil) medium and incubation for
1 h (chase) was performed as described.15 Microscopy pictures
were taken with the help of an Olympus IX-71 inverted microscope equipped with 100×NA 1.49 objective and a sCMOS
camera (PCO). The InsightSSI illumination system was equipped
with DAPI-, GFP-, mCherry- and Cy5-filters. SoftWoRx software (Applied Precision) was used to operate the microscope.
Z-stacks of 4 μm with 400 nm spacing were used for
constrained-iterative deconvolution (SoftwoRx).
Mup1 uptake assay
To analyse Mup1-GFP trafficking, 20 mg/mL methionine was
added to the medium subsequent to FM4-64 staining, and cells
were incubated for 1 h (chase) at 26°C and 38°C, respectively.
The reads obtained from the exome analysis of patients Z-II-1,
B-II-1 and C-II-1 were aligned (reference genome Hg19), and
variants were called and filtered (detailed in online
supplementary table S1). A small number of variants remained
for each patient, but given their similar clinical course and neuroradiological findings and their common ethnic background, we
assumed a founder mutation and focused on chr11:118951899
T>G, NM_021729.5 c. 2536T>G, p.Cys846Gly ( p.C846G) in
the VPS11 gene which was present in all the patients in a homozygous form. Among 3232 unrelated anonymous AJs, there were
20 carriers for the p.C846G mutation in the VPS11 gene, indicating a carrier rate of 0.6% in this group (Mark Daly, personal
communication). The variant was carried also by 11 of the
60383 individuals whose exome analyses were deposited at the
Exome Aggregation Consortium, Cambridge, Massachusetts,
USA (URL http://exac.broadinstitute.org; accessed April 2015);
no homozygotes were present in these cohorts.
We next searched within our genomic linkage data for
patients of AJ origin with white matter disease whose DNA
SNP genotyped homozygous regions that encompassed VPS11
and identified a fourth family, family S (figure 2A). The minimal
homozygous region shared by all the patients was
chr11:118759860–119569987 (47 SNP markers with identical
genotype in all the patients). Thus, eight patients from four
unrelated families of AJ origin were identified. The homozygous
p.C846G mutation in the VPS11 gene segregated with the
disease within each family (figure 2A).
As Vps11 is an essential component of HOPS and CORVET
complexes, which are required for the transport of cargo along
the endocytic pathway, we generated a homologous mutation,
Table 1 Clinical and radiological findings
Patient/gender/
current age
Developmental
stagnation (months)
B-II-1/F/20 years
6–8
B-II-3/F/16 years
8
S-II-2/F/17 years
Speech
Motor
development
Head
circumference
Tone
Epilepsy
Brain MRI
Turns over
−2 SD
Limb spasticity
−
Delayed myelination, thin CC
Sit without
support
None
−2 SD
Delayed myelination, thin CC
+
S-II-5/M/12 years
Z-II-1/F/13 years
3–6
4
None
None
None
None
−3 SD
−3 SD
Limb spasticity,
truncal hypotonia
Limb spasticity,
truncal hypotonia
Spasticity
Spasticity
−
3–4
Few
words
Few
words
None
Z-II-2/F/11.5 years
3
None
None
−3 SD
−
Z-II-5/M/1 year
2
None
None
Normal at birth
Limb spasticity,
truncal hypotonia
Hypotonia
Paucity of white matter, thin CC,
cerebellar atrophy
Delayed myelination, thin CC
Delayed myelination, paucity of
white matter, thin CC
Paucity of white matter, thin CC
+
C-II-1/M/13
months
2
None
None
Normal at
13 months
Hypotonia
−
−2 SD
−
+
Thin CC, large ventricles at
3 months
Thin CC, hypomyelination
CC, corpus callosum.
Edvardson S, et al. J Med Genet 2015;0:1–5. doi:10.1136/jmedgenet-2015-103239
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C952G, in yeast Vps11. We then expressed Vps11 wild type
and the C952G mutant from a centromeric plasmid in the
vps11Δ background. Both plasmids complemented the vacuole
fragmentation phenotype observed in the non-complemented
vps11Δ strain (figure 4A), indicating that HOPS function in
vacuole fusion is rescued (figure 4B). To identify subtle defects
along the endocytic pathway to the vacuole, we monitored the
transport of a methionine permease Mup1 as a GFP-tagged
protein from the plasma membrane to the lysosome-like
vacuole. Mup1-GFP transport is initiated when cells, which
were grown in the absence of methionine, are exposed to excess
methionine, and Mup1-GFP is eventually found in the vacuole
lumen. We observed that Mup1 uptake assay resulted in 14 of
146 (10%) wild-type cells displaying accumulation of endocytic
cargo in vesicular structures that correspond to the late endosome.17 In the corresponding vps11 mutant cells, 20 of 110
(18%) showed this accumulation, suggesting a defect in the
fusion of the late endosome to the vacuole.
Finally, we determined the activity of several lysosomal
enzymes in the plasma of patient C-II-1 and found slight reduction of β-galactosidase activity 6.1 nmol/h/mL (controls 11.2
±2.5), with near-normal activities of total hexosaminidase
388 nmol/h/mL (controls 546±84), and arylsulfatase A
124 nmol/h/mL (controls 131±53).
DISCUSSION
We report on eight patients with developmental delay, acquired
microcephaly and hypomyelination associated with homozygosity for a founder mutation in the VPS11 gene. The mutation,
identified independently in four unrelated families, segregated
with the disease in each family, resulted in exactly the same
neurological phenotype, affected a highly conserved residue
throughout evolution, and had a carrier rate of ∼1:160 in
people of AJ background.
Vps11 is an essential protein of the endosomal pathway. It is
part of HOPS and CORVET, two hexameric tethering complexes, which localise to lysosomes and endosomes, respectively.
Human VPS11 is a 921 amino acids protein, which consists of
three conserved domains: a predicted WD40 domain (AA
142-292) is likely a part of the N-terminal β-propeller as identified for the Vps18 protein,18 two clathrin domains (AA
417-536, 598-727), which presumably add up as part of a
C-terminal alfa-solenoid,19 a RING-finger domain (AA
821-860) and a C-terminal domain (AA 862-909). RING-finger
domains are made of six spaced cysteines [C-X(2)-C-X(9,39)C-X(1,3)-H-X(2,3)-[NCH]-X(2)-C-X(4,48)-C-X(2)-C] and typically bind two zinc atoms. The fourth spaced cysteine residue is
the mutated residue in our patients. Loss of Vps11 in zebrafish
manifests by oculocutaneous albinism, pericardial oedema, hepatomegaly and premature death underscoring Vps11 role in the
fish melanosome maturation.20 Studies in various yeast mutants
revealed that Vps11 is an essential component of the endosomal
system;21 vps11Δ null mutants exhibited defects in endosomal
and vacuolar delivery and in late endosome and vacuole fusion.
In contrast, a Vps11 mutant termed Vps11 926Δ that lacks only
the RING motif had a relatively selective defect at the docking
or fusion at the vacuole, but not at the endosome.
Coimmunoprecipitation experiments of the Vps11 mutant
revealed that the RING domain is not needed for HOPS assembly.22 It is, therefore, not surprising that the phenotype of the
yeast Vps11 C952G mutant, corresponding to the p.C846G
mutation in our patients, is relatively mild and restores the
vacuole morphology of the vps11Δ background. It also keeps
the endolysosomal pathway intact, but causes a mild accumulation of cargo in the late endosome. We speculate that in neuronal cells, this abnormality would attenuate the degradation of
plasma membrane receptors, thereby underlying the progressive
neuronal phenotype in our patients.
Figure 4 Homologous mutation in yeast Vps11 has moderate effect on endocytic transport to the lysosome-like vacuole. (A and B) Vacuole
morphology and transport of Mup1-GFP from the plasma membrane to the vacuole. Cells with a deletion in vps11, or those complemented with
plasmids encoding wild-type Vps11 or the C952G mutant were grown at 26°C as described in Methods. After addition of FM4-64, which stains
endosomes and vacuoles, the temperature-sensitive phenotype was induced by shifting cells with Vps11 wild type and mutant to 38°C (B). Pictures
were taken after staining and induction of the uptake of Mup1-GFP and FM4-64. (C) Quantification of the temperature-sensitive phenotype of cells
expressing Vps11 wild type and C952G shown in B. Dark grey bar shows the percentage of cells displaying no endocytic defect. Light grey bar
shows percentage of cells, which display accumulated Mup1-GFP and FM4-64 proximal to the vacuole. Quantification was done by counting n=256
cells and dividing them into two groups based on their phenotype. A representative result of three independent analyses, which gave similar results,
is shown.
4
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Defects in endosomal maturation are recently being unravelled in neurodegenerative disorders. In the autosomal dominant
neuropathy Charcot–Marie–Tooth disease type 2B, mutations in
the late endosomal Rab7 GTPase interfere with receptor trafficking, resulting in alteration in intracellular signalling events.23
Specifically, mutant Rab7 delays trafficking of epidermal growth
factor receptor (EGFR) to the lysosome, thereby slowing down
the process of receptor degradation, causing enhanced EGFR
signalling, and increased p38 and Erk1/2 activation.24 Excessive
endosome-to-lysosome trafficking in a HOPS-related manner
was recently shown to underlie the neurodegeneration in the fly
mutant of TBC1D24, which in human beings is associated with
epilepsy, deafness and intellectual disability.25–27
Given the requirement for the endosomal network in most
body systems, it is unclear why mutated VPS11 has such a selective effect on the brain only. The exclusive organ involvement
could be related to specific cargo affinity, to tissue-specific expression of various endosomal network-related proteins or to the
slow turnover of neuronal cells, which results in massive accumulations over extended periods of time. The latter explanation
would agree with recent findings on Rab7 mutants, which also
result in an adult-onset neurodegenerative disease, and similar to
our observations on the VPS11 mutant in yeast (figure 4), result
in a mild overall defect in transport.23 In summary, recessive
p.C846G pathogenic variants in the VPS11 gene are causative of
a novel endosomal network defect with clinical features of hypomyelination and marked developmental delay. p.C846G is an AJ
founder mutation, and given its considerable carrier frequency in
the AJ population (0.6%), we propose that it should be added to
the AJ carrier screening panel.
Acknowledgements We are grateful to Dr Mark Daly, the Broad Institute, Boston,
for carrier rate data and to the patients’ families for their cooperation. This work
was partly funded by the DFG (Deutsche Forschunggemeinschaft), UN111/6-1.
Contributors SE, CJ and DG undertook patient management, collected samples
and delineated the phenotype, analysed the data and wrote the paper. FG, JL, Ash
and AS a performed the experiments, analysed the data and wrote the paper. SE,
CJ, CU and OE conceived and designed the experiments, analysed the data and
wrote the paper, undertook patient management, collection of samples and
delineation of the phenotype.
Competing interests None declared.
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Patient consent Obtained.
Ethics approval
Provenance and peer review Not commissioned; externally peer reviewed.
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Hypomyelination and developmental delay
associated with VPS11 mutation in
Ashkenazi-Jewish patients
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Golan, Ann Saada, Avraham Shaag, Christian Ungermann and Orly
Elpeleg
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