Scandinavian Journal of Rheumatology

ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20

A homozygous mutation in the PSMB8

gene in a case with proteasome-associated
autoinflammatory syndrome

C Contreras-Cubas, A Cárdenas-Conejo, A Rodríguez-Velasco, H García-Ortiz,

L Orozco & V Baca

To cite this article: C Contreras-Cubas, A Cárdenas-Conejo, A Rodríguez-Velasco, H García-

Ortiz, L Orozco & V Baca (2017): A homozygous mutation in the PSMB8 gene in a case with
proteasome-associated autoinflammatory syndrome, Scandinavian Journal of Rheumatology, DOI:
10.1080/03009742.2017.1342273

To link to this article: http://dx.doi.org/10.1080/03009742.2017.1342273

Published online: 12 Sep 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=irhe20

Download by: [Australian Catholic University] Date: 12 September 2017, At: 11:19
 Scand J Rheumatol 2017;00:1–4 1

LETTER

A homozygous mutation in the PSMB8 gene in a case with proteasome-

associated autoinflammatory syndrome
C Contreras-Cubas1, A Cárdenas-Conejo2, A Rodríguez-Velasco3, H García-Ortiz1, L Orozco1, V Baca4
1
Immunogenomics and Metabolic Diseases Laboratory, National Institute of Genomic Medicine, SS, Mexico City, Mexico
2
Departament of Genetics, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico
3
Anatomic Pathology Service, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico
4
Department of Rheumatology, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico
Downloaded by [Australian Catholic University] at 11:19 12 September 2017

The term proteasome-associated autoinflammatory syn-
drome (PRAAS) has been proposed to encompass a
group of disorders caused by autosomal recessive muta-
tions in the inducible proteasome subunit β type 8 (PSMB8)
gene, which encodes the β5i subunit (1). However, PRAAS
has recently been associated with mutations in other pro-
teasome genes, such as PSMA3, PSMB4, PSMB9, and
proteasome maturation protein (POMP) (2). PRAAS
includes joint contractures, muscle atrophy, microcytic
anaemia, panniculitis-induced lipodystrophy syndrome
(3), Nakajo–Nishimura syndrome (4), Japanese autoin-
flammatory syndrome with lipodystrophy (5), and chronic
atypical neutrophilic dermatosis with lipodystrophy and
elevated temperature (CANDLE) syndrome (6). These syn-
dromes are characterized by early-onset skin eruptions,
recurrent fever, joint contractures, muscular atrophy,
lipodystrophy, hepatosplenomegaly, and basal ganglia cal-
cifications. Laboratory abnormalities include anaemia, ele-
vated acute-phase reactants, high levels of interleukin-6,
hypergammaglobulinaemia, and autoimmune abnormal-
ities (7). Here, we report the first case homozygous for the
c.274G > A, p.A92T mutation previously reported in a
compound heterozygous Hispanic patient who also had
the founder mutation c.224C > T, p.T75M (1).
A 2-year-old female Mexican patient with non-consan-
guineous parents was referred to our institution without
diagnosis. The mother previously had a spontaneous abor-
tion and a repaired cleft lip and palate. The patient was
delivered by caesarean section and had a cleft-lip repair at
5 months of age. At 3 months of age the patient developed
papular and nodular erythematous skin lesions associated
with recurrent fever. The skin lesions were painful and
itchy, presenting first in the lower extremities and then
generalized, and resulted in a hyperpigmented macule
upon healing. At 18 months of age, the patient developed
hepatosplenomegaly, and liver biopsy showed steatosis
with moderate portoportal fibrosis.
Upon physical examination, we found erythematous
papules and nodules on her palms and face and ulcera-
tion on her fingertips in addition to multiple residual
hyperpigmented skin lesions. Her facial features
included violaceous erythema and oedema of the eye-
lids, thick lips, and decreased fatty tissue in the face
(Figure 1A B). Partial lipodystrophy was also found in
the upper chest and upper limbs. She also had general-
ized lymphadenopathy, a protuberant abdomen with
umbilical hernia, and hepatosplenomegaly. No joint con-
tractures were observed, but bilateral knee arthritis and
swollen fingers and toes were noted. The patient’s height
and weight were below the third percentile and she was
both physically and developmentally delayed.
Abnormal laboratory findings included hypochromic
microcytic anaemia (haemoglobin 8.5 g/dL), thrombocy-
tosis (520 000 cells/mm3), and elevated serum aspartate
aminotransferase (105 UI/L) and alanine aminotransfer-
ase (160 UI/L). High serum triglycerides (356 mg/dL) and
low high-density lipoprotein cholesterol levels (14 mg/
dL) were measured. High levels of C-reactive protein
(54 mg/L), serum globulin (5.19 g/dL), immunoglobulin
G (IgG) (3513 mg/dL), IgM (292 mg/dL), IgE (851 IU/
mL), and thyroid stimulating hormone (6.3 mU/L) were
also measured. Immunological tests revealed positive
anti-nuclear, anti-cardiolipin, and anti-Sm antibodies.
Initially, complement C3 levels were normal but
decreased after disease progression. Skin biopsy revealed
a mixed perivascular, periadnexal, and interstitial infil-
trate composed of lymphocytes and plasma cells, leuco-
cytoclasis, and vasculitis. Brain computed tomography
revealed basal ganglia calcification (Figure 1C–F).
Because PRAAS was suspected, direct DNA sequencing
of PSMB8 was performed for the patient, mother, and
maternal grandparents. The patient was homozygous for
the previously reported missense mutation on exon 2
(c.274 G > A), whereas the mother and grandfather
were heterozygous (Figure 1G). Because the father was
not available, the relationship between the maternal
grandfather and grandchild was confirmed by DNA test-
ing. After genetic diagnosis of PRAAS, 1 mg/kg/day
prednisone was started with a good response regarding
the fever and skin lesions, but symptoms recurred

© 2017 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation

DOI: https://doi.org/10.1080/03009742.2017.1342273 www.scandjrheumatol.dk
 2 Letter

A B

C D F
Downloaded by [Australian Catholic University] at 11:19 12 September 2017

Grandfather Mother Patient

Figure 1. Clinical photographs of the proteasome-associated autoinflammatory syndrome (PRAAS) patient. (A) Facial features revealed a heliotrope-like
periorbital rash and oedema, erythematous papules, thick lips, and lipoatrophy. (B) Erythematous papules and nodules on her palms and wrists, and
ulceration on her fingertips. (C) Calcification of basal ganglia on cranial computed tomography. Histological findings revealed (D) periadnexal inflammatory
infiltrate and leucocytoclasis, (E) lymphocytic vasculitis with leucocytoclasis, and (F) an interstitial mixed infiltrate composed of lymphocytes and plasma
cells, most prominently in the deep reticular dermis (hematoxylin and eosin stain). (G) PSMB8 sequencing for all family members. Nucleotide
chromatograms of the affected region. The red arrow indicates the variation site on exon 2 (c.274 G > A).

following tapering. Thereafter, methotrexate and chloro- another hospital, dying 3 days later in the intensive care
quine were added without clinical improvement. At unit from aseptic meningitis of unknown cause.
4 years of age, she developed status epilepticus with To the best of our knowledge, this is the first PRAAS
generalized tonic–clonic seizures and was admitted to patient homozygous for the A92T mutation. Proteasomes

www.scandjrheumatol.dk
 Letter 3

Table 1. Comparison of clinical and laboratory findings in proteasome-associated autoinflammatory syndrome (PRAAS) patients
harbouring the p.A92T mutation.

Clinical and laboratory findings Our patient PRAAS patient reported in reference (1)

PSMB8 mutation p.A92T/p.A92T p.A92T/p.T75M

Age at onset 3 months 3 months
Outcome Died at 4 years of age Alive at 19 years old (age at diagnosis)
Low weight and height Yes Yes
Recurrent fever Yes Yes
Skin eruptions Erythematous papules and nodules; violaceous Erythematous papules and nodules
erythema and oedema of eyelids; fingertip ulcers
Alopecia Yes No
Vasculitis/leucocytoclasis Yes No
Lipodystrophy Yes Yes
Arthritis Yes Yes
Swollen fingers and toes Yes No
Perioral swelling Yes No
Prominent abdomen Yes No
Lymphadenopathy Yes No
Downloaded by [Australian Catholic University] at 11:19 12 September 2017

Hepatomegaly Yes Yes

Splenomegaly Yes Yes
Myositis/muscle atrophy Yes Yes
Low IQ Yes Yes
Seizures Yes No
Basal ganglia calcification Yes Yes
Anaemia Yes Yes
White blood cells Normal to mild leucocytosis initially and leucopenia Low normal range
with lymphopenia after disease progression
Platelet count Thrombocytosis initially and thrombocytopenia NS
after disease progression
Elevated AST and ALT Yes Yes
Dyslipidaemia Yes No
Elevated CPK No Yes
Elevated TSH Yes Yes
Elevated ESR/CRP Yes Yes
Autoantibodies ANA, ACL, and anti-Sm positive; anti-DNA, anti-Ro, ANA and ANCA positive
anti-La, and anti-RNP negative
Complement levels C3 levels normal initially and low after NS
disease progression
Hypergammaglobulinaemia High levels of IgG, IgM, and IgE High levels of IgG, IgM, and IgE
Cytokine levels ND High levels of IL-6 and IP-10

IQ, intelligence quotient; AST, aspartate aminotransferase; ALT, alanine aminotransferase, CPK, creatine phosphokinase;
TSH, thyroid-stimulating hormone; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ANA, anti-nuclear antibodies;
ACL, anti-cardiolipin; Ig, immunoglobulin; ANCA, anti-neutrophil cytoplasmic antibodies; IL, interleukin; IP, interferon-gamma-inducible
protein; ND, not determined; NS, not specified.

References
are protease complexes that play a critical role in main-
taining cellular function through the selective degradation
of ubiquitinated proteins. The p.A92T variant changes
residues that define the conformation of the S1 sub-
strate-specificity pocket, causing selective impairment of
chymotrypsin-like activity but not affecting maturation of
the β5i subunit and proteasome assembly (2). Mutations
in proteasome genes cause proteasome dysfunction,
which induces type I interferon transcription and drives
an inflammatory response and autoimmunity (2).
Although our case shared several clinical symptoms and
laboratory findings with the previously reported com-
pound heterozygous patient carrying the A92T mutation
(Table 1), our patient’s outcome shows that homozygos-
ity for this mutation is associated with a more severe
clinical course.
1. McDermott A, Jesus AA, Liu Y, Kim P, Jacks J, Montealegre
Sanchez GA, et al. A case of proteasome-associated auto-inflam-
matory syndrome with compound heterozygous mutations. J Am
Acad Dermatol 2013;69:e29–32.
2. Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q,
et al. Additive loss-of-function proteasome subunit mutations in
CANDLE/PRAAS patients promote type I IFN production. J Clin
Invest 2015;125:4196–211.
3. Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez
MD, Sousa AB, et al. PSMB8 encoding the β5i proteasome sub-
unit is mutated in joint contractures, muscle atrophy, microcytic
anemia, and panniculitis-induced lipodystrophy syndrome. Am J
Hum Genet 2010;87:866–72.
4. Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T,
Mizushima T, et al. Proteasome assembly defect due to a protea-
some subunit beta type 8 (PSMB8) mutation causes the autoin-
flammatory disorder, Nakajo-Nishimura syndrome. Proc Natl
Acad Sci USA 2011;108:14914–19.

www.scandjrheumatol.dk
 4 Letter

5. Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishi- clinical presentations, diagnosis, and management. Int J Dermatol
zawa M, et al. A mutation in the immunoproteasome subunit 2015;54:121–9.
PSMB8 causes autoinflammation and lipodystrophy in humans.
J Clin Invest 2011;121:4150–60.
6. Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al.
Mutations in proteasome subunit β type 8 cause chronic atypical Vicente Baca, Department of Rheumatology, Pediatric Hospital
neutrophilic dermatosis with lipodystrophy and elevated tempera- Medical Center SXXI, Av Cuauhtemoc 330, Col Doctores, CP 06720,
ture with evidence of genetic and phenotypic heterogeneity. Mexico City, Mexico.
Arthritis Rheum 2012;64:895–907. E-mail: vicbaca@prodigy.net.mx
7. McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L. Proteasome-
associated autoinflammatory syndromes: advances in pathogeneses, Accepted 11 June 2017
Downloaded by [Australian Catholic University] at 11:19 12 September 2017

www.scandjrheumatol.dk