(2021) 9:106
Sainouchi et al. acta neuropathol commun
https://doi.org/10.1186/s40478-021-01202-w

LETTER TO THE EDITOR

Open Access

A novel splicing variant of ANXA11
in a patient with amyotrophic lateral sclerosis:
histologic and biochemical features
Makoto Sainouchi1†, Yuya Hatano2†, Mari Tada1*† , Tomohiko Ishihara2*†, Shoichiro Ando2, Taisuke Kato3,
Jun Tokunaga2, Gaku Ito2, Hiroaki Miyahara1, Yasuko Toyoshima1, Akio Yokoseki2, Tetsutaro Ozawa4,
Kohei Akazawa5, Osamu Onodera2 and Akiyoshi Kakita1

To the editor
Mutations in the annexin A11 gene (ANXA11) havebeen shown to cause amyotrophic lateral sclerosis(ALS) [6]. Annexin A11 is a C­ a2+-dependent phospholipid-binding protein that possesses an N-terminal low-complexity domain and C-terminal repeatedannexin domains, being involved in C
­ a2+ signaling,cell division, apoptosis, and vesicle trafficking [3, 5,
8]. Recent studies have indicated that ALS-related
ANXA11 mutations enhance aggregation propensity,
leading to dysregulation of intracellular C­ a2+ homeostasis and RNA granule transport [3, 5, 6].
The clinical phenotypes of ANXA11-mutated ALS
vary, and differ even in patients harboring the same
mutation [6, 7, 9]. Autopsy findings of two patients
harboring N-terminal ANXA11 mutation have beenreported. One patient with p.D40G ANXA11 mutation showed the features of classical ALS [6], while theother with p.G38R ANXA11 mutation showed thoseof ALS-TDP with frontotemporal lobar degeneration (FTLD)-TDP type A [4, 7]. Both patients showed
aggregation of 43 kDa TAR-DNA-binding protein(TDP-43) and annexin A11 in neurons (Table 2).
*Correspondence: tadamari@bri.niigata-u.ac.jp; ishihara@bri.niigata-u.ac.jp†
Makoto Sainouchi and Yuya Hatano contributed equally to this work.
†
Mari Tada and Tomohiko Ishihara contributed equally to this work.
1
Departments of Pathology, Brain Research Institute, Niigata University,
1‑757 Asahimachi, Chuo‑ku, Niigata 951‑8585, Japan2
Departments of Neurology, Brain Research Institute, Niigata University,
1‑757 Asahimachi, Chuo‑ku, Niigata 951‑8585, Japan
Full list of author information is available at the end of the article

However, the variety of neuropathologic features,
including the distribution and morphology of TDP43- or annexin A11-immunoreactive (ir) inclusions,in patients with ANXA11 mutations remain to be further clarified. Here, we investigated the clinicopathologic features of a Japanese patient with sporadic ALS
harboring a novel splicing mutation in the annexin
domain of ANXA11, and the functional significance ofthe mutation.
A 57-year-old man, who had no family history ofneurologic disorders, presented with progressive limb
weakness and stiffness, followed by muscle fasciculations, pyramidal signs, dysphagia and dysarthria. No
dementia was noted. He died suddenly 19 months
after disease onset. His detailed clinical features aredescribed in the Additional File.
The neuropathologic features were consistent with
ALS. Neuronal loss and gliosis were restricted to themotor cortex, brainstem motor nuclei, and spinal
anterior horns (Fig. 1a–c, e–h; Table 1). The corticospinal tract in the spinal cord showed severe degeneration (Fig. 1d). Bunina bodies were occasionallyfound in the lower motor neurons (Fig. 1i, j). Phosphorylated TDP-43 (pTDP-43)-ir neuronal and oligodendroglial cytoplasmic inclusions (NCIs and GCIs,
respectively) were evident in the above-mentioned
areas (Fig. 1k, o, p, motor cortex; q, white matter adjacent to the motor cortex; l, r, hypoglossal nucleus; s,anterior horn of the lumbar cord) and several others(Fig. 1m, subthalamic nucleus; n, pontine nucleus) but© The Author(s) 2021, corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver(http://​creat​iveco​mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a
credit line to the data.

Sainouchi et al. acta neuropathol commun(2021) 9:106

not in the hippocampus or temporal cortex (Table 1).
Morphologically, the pTDP-43-ir NCIs were granular
and/or filamentous (Fig. 1o, p) in all areas where NCIs
were observed, and characteristically those in thelower motor neurons were thick skein-like, or tubeshaped (Fig. 1r, s).
Genetic screening of ALS-related mutations throughwhole-exome sequencing revealed a heterogeneous
splice site mutation, c. 1086+1G>A, in the ANXA11
gene (Fig. 2a), which has an allele frequency of 0.08%
in the Human Genetic Variation Database (HGVD),
and has not been documented in the Exome Aggregation Consortium (ExAC). On the other hand, no variants which are less than 0.1% frequency were found inany of the other ALS-related genes (See Supplementary methods). A splice site prediction program (NetGene2, http://​w ww.​cbs.​dtu.​dk/​s ervi​ces/​NetGe​ne2/)
correctly recognized the splice donor site of intron 11
in the wild type, but not in the mutant sequence, indicating that the mutation disrupts the splice donor site.
Sequencing of the reverse transcription PCR productsof ANXA11 mRNA obtained from the autopsied brain
showed an aberrant transcript containing a 72-bp
insertion between exons 11 and 12 that resulted in theinsertion of 24 amino acids (Fig. 2b). Using the structure predictive tool, PSIPRED 4.0 (http://​bioinf.​c s.​
ucl.​ac.​uk/​p sipr​e d/), the inserted amino acid sequence
was predicted to create new alpha helixes. However,no new motifs were identified in the aberrant proteinusing a motif finder (Pfam 34.0, http://​pfam.​xfam.​org/ and HMMER v3.3.2, http://​hmmer.​org/). Hydrophobicity prediction [2] using ExPASy (https://​web.​expasy.​org/​prots​c ale/) and protein disorder analysis
using PrDOS (http://​prdos.​hgc.​jp/​cgi-​bin/​top.​cgi) [1]revealed that the aberrant annexin A11 had increasedhydrophobicity (Fig. 2c, upper panel) and disorderprobability (Fig. 2c, lower panel), respectively, aroundthe inserted 24-amino-acid site compared with wild
type. We then undertook cellular experiments using
HEK293T cells transfected with the 72-bp inserted

Page 2 of 9

mutant, and wild type GFP-tagged ANXA11 (GFPANXA11MT and GFP-ANXA11WT, respectively) constructs. Solubility fractionation of the cells transfectedwith GFP-ANXA11 constructs, followed by Western
blotting using antibodies for annexin A11 (Fig. 2d,left) and GFP (Fig. 2d, right) revealed that GFPannexin ­A11MT formed detergent-resistant insoluble
species. Furthermore, cells expressing GFP-annexin­A11WT showed mainly a diffuse nuclear and cytoplasmic distribution of GFP, whereas cells expressing
GFP-annexin ­A11MT showed cytoplasmic aggregation
significantly frequently (Fig. 2e, f ).
Indeed, the present patient had many annexin
A11-ir skein-like NCIs in the lower motor neurons(Fig. 3a, b). In contrast, sparse dot-like cytoplasmic
staining (Fig. 3c) and rare filamentous inclusions wereobserved in the lower motor neurons of ALS patientswith no ANXA11 mutation. Such sparse dot-like cytoplasmic staining was also observed in controls, andnot only in motor neurons (Additional file 1: Fig. 1).
These findings indicated that annexin A11-ir NCIs
are not completely specific, but characteristic to
ANXA11-mutated patients. In the motor cortex, only
a few, irregularly shaped or round, small NCIs wereobserved (Fig. 3d, e). Filamentous NCIs were also evident in several regions where pTDP-43-ir NCIs werealso present (Fig. 3f, h, i, Table 1). Annexin A11 aggregated preferentially in neurons, although a few GCIs
were observed (Fig. 3g). Double-labeling immunofluorescence for pTDP-43 and annexin A11 revealed thatannexin A11 and pTDP-43 were partially co-localized in skein-like NCIs, and a few GCIs in the anterior horns (Fig. 3j, k), but not in small annexin A11-ir
NCIs in the motor cortex (Fig. 3l). Annexin A11-irskein-like NCIs in the anterior horns were frequently
well labeled for p62 (Fig. 3m). Details of methods are
in Supplementary methods, and the primary antibodies used are listed in Supplementary table 1 in Additional file 1.

(See figure on next page.)
Fig. 1 Neuropathologic findings. a, b The motor cortex shows neuronal loss and gliosis more prominently in a the lateral side than b the medial
side. Some Betz cells are preserved only in the medial side of the motor cortex (arrowheads in b, c). c Macrophage accumulation in a Betz cell-sizedhole (arrow in c), indicating ongoing neuronal degeneration, is evident in the medial side. d Myelin pallor in the bilateral lateral columns of thecervical and lumbar cord, and the left anterior column of the cervical cord, which indicate degeneration of the pyramidal tracts. Atrophy of theanterior horns is also evident in the cervical cord. e–h Severe neuronal loss and gliosis in e the cervical anterior horn, and f–h facial nucleus(arrows, atrophic neurons; arrowheads, reactive astrocytes; g and h, high magnification images of the square in f; h, GFAP-immunohistochemistry).
i, j Bunina bodies in the remaining motor neurons of the facial nucleus (j, cystatin C-immunohistochemistry). k–s Phosphorylated TDP-43(pTDP-43)-immunohistochemistry. Several pTDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) and glial cytoplasmic inclusions(GCIs) in k the motor cortex, l hypoglossal nucleus and m subthalamic nucleus. n NCIs in the pontine nucleus. o Granulofilamentous and (left inp) filamentous NCIs and (right in p) GCI in the motor cortex. q GCIs in the white matter adjacent to the motor cortex. r Thick skein-like NCI in the
hypoglossal nucleus. (s) Tube-shaped NCI in the anterior horn of the lumbar cord. Bar = 190 µm for a, b; 35 µm for c, g, h; 3 mm for d; 75 µm for e, f;
10 µm for i, j, o–r; 50 µm for k–n; 15 µm for sSainouchi et al. acta neuropathol commun(2021) 9:106

Page 3 of 9+**White matter*

++

−

−

−/−

−

Caudate nucleus/putamen

Thalamus−−−Subthalamic nucleus

Oculomotor nucleus

Locus ceruleus−

Pontine nucleus−/−**

Cortex/white matter++/++/−**

NA

NA+/+/++

−

−/NA

+

+

++

+

+

++

+

+

−

−

+

−

−

+/+

−

−

−

+

−

NA

++

+/+/+

−/+/+

++/++/++

−

−/+

+

+

++

−

+

+

−

−

−

+

+

−

−

−/+

−

−

−

−

−

++

++

−

NA

NA

+/+/++

−

−/NA

+

+

++

−

+

++

+

−

−

−

−

−

−

−/+

−

−

−

−

−

NA

+

−

NCIs

−

Annexin A11

NCIs

GCIs

pTDP-43

−/−/−

−/−/−

−/−/+

−

−/−

−

−

−

−

−

−

−

−

−

−

−

−

−

−/+

−

−

−

−

−

−

−

−

GCIs

(2021) 9:106*, White matter adjacent to the motor cortex; Neuronal loss (**, degeneration with macrophage infiltration): −, none; +, mild to moderate; ++, severe; NCIs and GCIs: −, none; +, rare (1–4 /10 high-power fields); ++,occasional (≧ 5/10 high-power fields); pTDP-43, phosphorylated 43 kDa TAR DNA-binding protein; NCIs, neuronal cytoplasmic inclusions; GCIs, glial cytoplasmic inclusions; NA, not applicable; C, cervical cord; Th, thoracic
cord; L, lumbar cord

Anterior funiculus (C/Th/L)

Lateral funiculus (C/Th/L)++/++/+**++/++/+

Anterior horn (C/Th/L)

Spinal cord−

Dentate nucleus

Cerebellum

−

−

++

+

Reticular formation

Inferior olivary nucleus

Hypoglossal nucleus

Ambiguous nucleus+++

Trigeminal motor nucleus

Facial nucleus−

Substantia nigra

Brainstem−

Globus pallidus−−

Amygdaloid nucleus

Ammon/dentate gyrus

Subcortical area−

Occipital cortex

Parietal cortex−

Temporal cortex

Motor cortex

Frontal cortex

Cerebrum

Neuronal loss

Table 1 Distribution of neuronal loss and pTDP-43- and annexin A11-immunoreactive NCIs and GCIs

Sainouchi et al. acta neuropathol commun
Page 4 of 9

Sainouchi et al. acta neuropathol commun(2021) 9:106

The neuropathologic features of this patient wereindistinguishable from those of ALS without known
mutations, except for the presence of annexin A11-ir
NCIs, being similar to the previously reported patientwith ANXA11 mutation (Table 2) [6].
On the other hand, genetic screening revealed thenovel splicing mutation in the C-terminal of ANXA11,
and the in silico analysis and cellular experimental findings indicated that the aberrantly spliced
transcript induced cytoplasmic accumulation andenhanced the aggregation propensity of annexin
A11, suggesting that the mutation had pathogenicity. Functional studies of ALS-related ANXA11
mutations have shown that both N-terminal andC-terminal mutations induced abnormal phase separation to form aggregates, leading to the functional
defects of annexin A11 [3, 5]. Similar toxic-gain-offunction mechanisms might have contributed to ALS
pathogenesis in this patient.
Morphologically, the annexin A11-ir NCIs in thispatient differed slightly from those in the previous
patients with N-terminal ANXA11 mutation [6, 7].
We observed skein-like, filamentous, and small roundinclusions but not the conglomerated, round, or basket-like large inclusions that had been present in theprevious patients. Such differences might depend on
the specific location of each mutation, since the disorder probability is lower in the annexin domain thanin the N-terminal low complexity domain (Fig. 2c),Page 5 of 9which is responsible for protein aggregation [5]. Furthermore, the co-localization of annexin A11 andp62 in NCIs was clear in this patient, but not in theprevious patient with N-terminal ANXA11 mutation[7], implying that clear and frequent superposition ofannexin A11 and p62 might be specific for the patientswith C-terminal ANXA11 mutation.
Interestingly, annexin A11 was aggregated predominantly in neurons and only very sparsely in glial cells,
and topographically, in the brainstem motor nuclei
and spinal anterior horns rather than the motor cortex, whereas TDP-43 was aggregated in both neurons
and glial cells, and frequently in both the upper andlower motor systems. Thus, TDP-43 aggregated evenin annexin A11-negative cells, especially glial cells.
Similarly, TDP-43 aggregation in annexin A11-negative cells had also been noted in the two previously reported patients with N-terminal ANXA11
mutation [6, 7]. Together with these previous studies, our present findings indicate that annexin A11
aggregation propensity is probably dependent oncell type, and that annexin A11 aggregation is notindispensable for triggering TDP-43 aggregation andneurodegeneration.
Overall, we have confirmed the pathogenicity of thisnovel mutation in the C-terminal region of ANXA11.
Neuropathologic findings suggested a cell typedependent annexin A11 aggregation propensity. Further studies are needed to confirm this possibility.

(See figure on next page.)
Fig. 2 Position of the identified ANXA11 mutation and biological characteristics of the mutant annexin A11. a Annexin A11 protein domains andthe position of mutations identified in patients with amyotrophic lateral sclerosis (ALS). Mutations found in the previous studies are in black andthat of the present patient is in red. b An aberrant ANXA11 mRNA splicing as a consequence of the c.1086 + 1G > A mutation. Gel electrophoresis
shows the reverse transcription PCR products from the autopsied brain of the present patient (Pt), patients with sporadic ALS harboring no ANXA11
mutations (SALS), and controls. The lane of Pt contains two different bands. Sequencing results show that the band located at 339 bp implies anormal transcript, and that located at 411 bp implies an aberrant transcript caused by 72-bp insertion between exons 11 and 12, numbered on
the basis of ENSEMBL ANXA11-203. The inserted sequence results in a 24-amino-acid insertion. c Hydrophobicity and protein disorder predictions.
Upper panel: Hydropathy plot [2] of the aberrant annexin A11 (MT) obtained using ExPASy shows increased hydrophobicity around the inserted
24-amino-acid site. Lower panel: Disorder profile plot of the aberrant annexin A11 (MT) obtained with PrDOS [1] shows increased disorderprobability around the inserted 24-amino-acid site compared with that of the wild type (WT), indicating that the aberrant splicing could affect thestability and function of annexin A11. d Solubility fractionation of the cells transfected with GFP-tagged ANXA11 (GFP-ANXA11) constructs, followedby Western blotting using antibodies for (left) annexin A11 and (right) GFP. The wild type annexin A11 protein is predominantly soluble, whereas
the mutant construct shows a prominent increase in the insoluble fraction. Red arrowhead: wild type (WT) and mutant (MT) GFP-annexin A11.
Black arrowhead: endogenous annexin A11. β-Actin: loading control. e GFP-annexin A11 localization in HEK293T cells. Cells are classified according
to GFP-annexin A11 localization patterns, i.e. cytoplasmic aggregation, and diffuse distribution. Bar = 10 µm for all images in e. f Proportion ofcells showing each GFP-annexin A11 localization pattern. The proportion of cells showing cytoplasmic aggregation is significantly higher, and thatof cells showing diffuse distribution is significantly lower in cells expressing GFP-annexin A­ 11MT than in those expressing GFP-annexin ­A11WT (*,p < 0.002; Mann–Whitney U test)

Sainouchi et al. acta neuropathol commun(2021) 9:106

Page 6 of 9

Sainouchi et al. acta neuropathol commun(2021) 9:106

Page 7 of 9

Fig. 3 Expression of annexin A11 in autopsied CNS tissue. a–i Annexin A11-immunohistochemistry. a Annexin A11-immunoreactive (ir) skein-likeneuronal cytoplasmic inclusions (NCIs) in the anterior horn and b hypoglossal nucleus. c Small dot-like staining pattern in an anterior horn cellfrom a patient with amyotrophic lateral sclerosis without ANXA11 mutation. d Small irregular-shaped and e round NCIs in the motor cortex. f
Filamentous NCI and g glial cytoplasmic inclusion (GCI) in the putamen. h Filamentous NCI in the pontine nucleus and i inferior olivary nucleus.
j–l Double-label immunofluorescence with annexin A11 and pTDP-43. j Annexin A11 and pTDP-43 are partially co-localized in the skein-like NCI.
k Weak immunoreactivity of annexin A11 in pTDP-43-ir GCI. j, k, lumbar anterior horn. l Annexin A11-ir and pTDP-43-negative small, irregularly
shaped and short linear NCIs, and pTDP-43-ir and annexin A11-negative dystrophic neurite in the motor cortex. m Annexin A11-ir and p62-ir NCI in
the lumbar anterior horn. j–l green, annexin A11; red, pTDP-43, m green, annexin A11; red, p62. Bar = 60 µm for a, b; 30 µm for c, d; 10 µm for e–i, l;
15 µm for j, m; 6 µm for kSainouchi et al. acta neuropathol commun(2021) 9:106

Page 8 of 9

Table 2 Clinical and neuropathologic features of patients harboring ANXA11 mutation
Present patient

Patient with p.D40G [6]Patient with p.G38R [7]Age at onset (years)

57

72

60’sa

Disease duration (months)

19

36

naa

Initial symptom

Limb

BulbarLimb

Cognitive impairment or FTD

−

−

+

+

na

+

−

na

Clinical features

Neuropathologic phenotype

ALS-TDPALS-TDPALS-TDP with FTLD-TDP type A

Neuronal loss
Motor cortex
Lower motor neurons
Frontotemporal cortex
Degeneration of CST
Bunina bodypTDP-43-ir NCIs/GCIs
Annexin A11-ir NCIs/GCIs
Morphology of annexin A11-ir NCIs
Co-localization of pTDP-43 and annexin A11

+

+

+

+

+/+

+/na

Skein-like, filamentous,
small round

Skein-like, filamentous, large-caliber andtube-shaped, large basket-like

+

+/few

− or +

na
+/na
−

na
+

+

+

+/+

+/na

Tube-shaped, large conglomerate, large round− or ++, present; −, absent; a, among 3 patients harboring p.G38R ANXA11 mutation, the autopsied patient was not identified in the reference [7]; FTD, frontotemporaldementia; ALS, amyotrophic lateral sclerosis; FTLD, frontotemporal lobar degeneration; na, not available; CST; corticospinal tract; pTDP-43, phosphorylated 43 kDa TAR
DNA-binding protein; ir, immunoreactive

Declarations
Abbreviations
ALS: Amyotrophic lateral sclerosis; pTDP-43: Phosphorylated 43 kDa TAR-DNAbinding protein.

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s40478-​021-​01202-w.
Additional file 1. Details of methods and case presentation, a list of the
primary antibodies used (Supplementary Table 1), and the representative
images of annexin A11 immunohistochemistry in CNS tissue of controls(Supplementary Figure 1).
Acknowledgements
Not applicable.
Authors’ contributions
MT, TI, OO and AK designed research project. MS, MT, HM, YT and AK performed pathological analysis. YH, TI, SA, TK, AY and OO designed the molecularexperiments and performed those. JT, GI, TO and OO collected clinical data. KA
managed statistical analyses. MS, YH, MT, TI, OO and AK discussed the results
and drafted the manuscript for intellectual content.
Funding
Supported in part by JSPS grants-in-aid for Scientific Research to MT(19K07972), AK (19H01061, 19H05559), and TI (17K09750), Grants-in Aid fromthe Research Committee of CNS Degenerative Diseases, Research on Policy
Planning and Evaluation for Rare and Intractable Diseases, Health, Labour andWelfare Sciences Research Grants, the Ministry of Health, Labour and Welfare,Japan to AK and OO.
Availability of data and materials
The datasets used and analyzed during the current study available from thecorresponding author on reasonable request.

Ethics approval and consent to participate
The present study was approved by the Ethics Committee of Niigata University (G2018-0033 and G2015-0781). Written informed consent for autopsy
including the use of tissues for research purposes was obtained from thepatients’ family.
Consent for publication
Family members have consented to publication.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Departments of Pathology, Brain Research Institute, Niigata University, 1‑757
Asahimachi, Chuo‑ku, Niigata 951‑8585, Japan. 2 Departments of Neurology, Brain Research Institute, Niigata University, 1‑757 Asahimachi, Chuo‑ku,
Niigata 951‑8585, Japan. 3 Department of System Pathology for Neurological
Disorders, Brain Science Branch, Brain Research Institute, Niigata University,
Niigata, Japan. 4 Department of Neurology, Uonuma Institute of Community
Medicine, Niigata University Medical and Dental Hospital, 4132 Urasa, Minamiuonuma, Niigata 949‑7302, Japan. 5 Department of Medical Informatics,
Niigata University Medical and Dental Hospital, 1‑754 Asahimachi, Chuo‑ku,
Niigata 951‑8520, Japan.
Received: 2 March 2021 Accepted: 17 May 2021

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