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Mini Review
Autoimmune lymphoproliferative syndrome
Umberto Dianzani, Ugo Ramenghi
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Sciences,
'A. Avogadro' University of Eastern Piedmont, via Solaroli 17, I-28100 Novara, Italy
Published in Atlas Database: July 2006
Online updated version: http://AtlasGeneticsOncology.org/Kprones/AutoimmLymphoID10116.html
DOI: 10.4267/2042/38370
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The mutation mostly hits the Fas gene (ALPS type-Ia),
but rare mutations of the Fas ligand gene (ALPS typeIb) or the caspase-10 gene (ALPS-type-IIa) gene have
also been described. Two siblings carrying a
homozygous mutation of the caspase-8 gene displayed
ALPS plus hypogammaglobulinemia and increased
susceptibility to infections; this disease has been named
caspase-8 deficiency, but some authors included it in
ALPS as ALPS type-IIb.
Caspase-8 and caspase-10 are involved in Fas
signalling.
Some authors used the term ALPS type-III to name the
disease caused by unknown mutations hitting the Fas
signalling pathway, others used it to name ALPS
displayed by patients with normal Fas function.
Rieux-Laucat described a subgroup of patients carrying
somatic mutations of the Fas gene in a subset of
peripheral lymphocytes (mosaic ALPS type-Ia or ALPS
type-Iam).
Since most patients with ALPS-Ia are heterozygous, the
term ALPS type-0 has been used to name the rare and
aggressive disease caused by homozygous mutations of
the Fas gene.
The genetic background may influence the disease
onset. Variants of the gene of perforin can act as
predisposition factors.
Identity
Other names: ALPS
Inheritance: autosomal dominant or recessive
Clinics
Phenotype and clinics
Paediatric onset with:
1) autoimmunity, that is predominantly haematological,
but any other autoimmunity can be displayed.
2) enlargement of the spleen and/or lymph nodes due to
accumulation of polyclonal lymphocytes.
3) peripheral blood expansion of T cells expressing the
TCRalpha/beta but not CD4 and CD8 (double-negative
T cells).
4) decreased function of the Fas death receptor.
Neoplastic risk
Increased risk of lymphomas.
Treatment
Vigorous immune supresión.
Evolution
Autoimmunity may remit in adulthood but
lymphoproliferation generally persists. Increased risk
of lymphomas in adulthood.
TNFRSF6
Prognosis
Location: 10q24.1
DNA/RNA
Description: encoded in 9 exons spanning 25 Kb.
Protein
Description: protein of 320 aa. Several isoforms
originating from alternative splicing have been
described. It contains three Cysteine-rich Domains and
one Death Domain.
Good on survival, but autoimmune haemolytic anaemia
may be occasionally lethal.
Genes involved and Proteins
Note: The disease is due to inherited defects decreasing
function of the Fas (CD95) death receptor, involved in
switching off the immune response by triggering
apoptosis of activated lymphocytes.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
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Autoimmune lymphoproliferative syndrome
Dianzani U, Ramenghi U
Expression: expressed by activated lymphocytes, but
also in multiple tissues and cell types.
Localisation: type-1 transmembrane protein.
Function: death receptor. It triggers apoptosis upon
ligation by its ligand (Fas ligand, FasL). It is involved
in switching off the immune response and cellmediated cytotoxicity.
Homology: Belongs to the tumor necrosis factor
receptor family, subgroup pf death receptor.
Mutations
Germinal: multiple loss-of-function mutations have
been reported in ALPS. They may decrease Fas
expression or cause expression of receptors with
dominant negative activity on Fas function. Mutations
in the death domain have the highest penetrance.
Somatic: somatic mutations of the Fas gene have been
reported in ALPS type-Iam.
Protein
Description: protein of 496 amino acids. Several
isoforms deriving from alternative splicing have been
described.
Expression: ubiquitous.
Localisation: cytosolic.
Function:
cystein-aspartate
protease
(caspase)
triggering apoptosis. It binds to the adapter molecule
FADD that associates with the intracytoplasmic tail of
death receptors such as Fas and triggers the extrinsic
pathway of apoptosis.
Mutations
Germinal: homozygous R248W substitutions has been
described in two siblings with ALPS plus
immunodeficiency. The mutated protein lost the
enzyme activity.
PRF1
FasL
Location: 10q22
Note: biallelic mutations of PRF1 cause the familial
hemophagocytic lymphohistiocytosis (HLH), an
immune deficiency ascribed to decreased capacity of
cytotoxic lymphocytes (CD8+ T cells and NK cells) to
kill virus-infected cells.
DNA/RNA
Description: encoded in 3 exons spanning 5.4 Kb.
Protein
Description: protein of 436 aa.
Expression: expressed by cytotoxic effector
lymphocytes (activated cytototoxic T cells and NK
cells).
Localisation: it is stored in the lytic granules and
secreted against the target cell.
Function: it polymerizes on the membrane of target
cells and forms pores.
Homology: High sequenze homology to the C9
complement component.
Mutations
Germinal: several PRF1 mutations have been
associated with HLH and lymphomas. These mutations
can inhibit either expression or function of perforin.
A heterozygous N252S amino acid substitution has
been described in one patient with ALPS type-Ia (i.e.
carrying also a heterozygous mutation of the Fas gene)
and one patient with ALPS type-III (i.e. with defective
Fas function caused by an unknown gene alteration). It
has been suggested that the PRF1 mutation may
cooperate with the mutation hitting the Fas system in
inducing ALPS development.
Location: 1q23
DNA/RNA
Description: encoded in 4 exons spanning 7.8 Kb.
Protein
Description: protein of 281 aa.
Expression: activated cytotoxic cells (CTL and NK)
and TH1 cells, but also expressed in other tisúes.
Localisation: type II transmembrane protein.
Function: triggers apoptosis of Fas-expressing cells.
Mutations
Germinal: two patients with ALPS type-Ib have been
described to date. One carried a 84-bp deletion in exon
4 causing a 28-aa in-frame deletion. The other carried a
A247E substitution in exon 4. Both mutations
decreased FasL function.
CASP10
Location: 2q33-q34
DNA/RNA
Description: encoded in 9 exons spanning 37 Kb.
Protein
Description: protein of 479 amino acids.
Expression: ubiquitous.
Localisation: cytosolic.
Function:
cystein-aspartate
protease
(caspase)
triggering apoptosis. It is involved in the extrinsic
pathway of apoptosis.
Mutations
Germinal: heterozygous L285F and I406L substitutions
have been detected in 2 patients with ALPS type-IIa.
References
CASP8
Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA,
Lin AY, Strober W, Lenardo MJ, Puck JM. Dominant interfering
Fas gene mutations impair apoptosis in a human autoimmune
lymphoproliferative syndrome. Cell 1995;81:935-946.
Location: 2q33-q34
DNA/RNA
Description: encoded in 10 exons spanning 54 Kb.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
303
Autoimmune lymphoproliferative syndrome
Dianzani U, Ramenghi U
Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM,
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This article should be referenced as such:
Dianzani U, Ramenghi U. Autoimmune lymphoproliferative
syndrome. Atlas Genet Cytogenet Oncol Haematol.2006;
10(4):302-304.
Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM,
Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
304