SDHA
In databases :
Gene locus :
5p15
Protein name:
Succinate
dehydrogenase complex, subunit A, flavoprotein variant
Protein Size:
664 amino acids; about 73 kDa
SDHAF2
In databases :
Gene locus:
11q12.2
Protein name:
Succinate dehydrogenase complex assembly
factor 2
Protein Size:
166 amino acids; about 20 kDa
SDHB
In databases :
Gene locus:
1p36.1-p35
Protein name:
Succinate dehydrogenase complex, subunit
B, iron sulfur (Ip)
Protein size:
280 amino acids; about 32 kDa
SDHC
In databases :
Gene locus :
1q23.3
Protein name:
Succinate dehydrogenase complex, subunit C, integral
membrane protein, 15kDa
Protein size:
169 amino acids; about 19 kDa
SDHD
In databases :
Gene
locus :
11q23
Protein
name :
Succinate dehydrogenase complex,
subunit D, integral membrane protein
Protein Size :
159
amino acids; about 17 kDa
TMEM127
In databases :
Gene
locus:
2q11.2
Protein
name:
transmembrane protein 127
Protein
Size:
238 amino acids; about 26 kDa
Function:
SDH is part of the mitochondrial electron
transport chain (complex II, succinate-ubiquinone oxidoreductase) and catalyses
the oxidation of succinate to fumarate in the Krebs cycle. Subunits A and B of
this complex (SDHA, SDHB) constitute the catalytic core of the enzyme, while
SDHC with SDHD anchor the complex to the matrix face of the mitochondrial inner
membrane. SDHAF2 is an SDH cofactor that appears to be required for SDHA
flavination, stability of the SDH complex, and therefore the function of the
SDH enzyme. Abnormal SDH function due to mutations of nuclear DNA encoding for
one of its subunits results in two completely different phenotypes. Defects in
SDHA cause metabolic neurodegenerative disorders like congenital Leigh syndrome
and late-onset optic atrophy, ataxia and myopathy, whereas SDHB, SDHC, and SDHD
mutations predispose to familial PGL. The molecular and cellular mechanisms
linking these latter SDHx mutations and tumorigenesis have not been fully
elucidated. Also, the pathophysiology of distinct clinical phenotypes
associated with abnormalities in different SDH subunits remains to be
unraveled.
TMEM127 is a transmembrane protein that
control cell proliferation acting as a negative regulator of TOR signaling
pathway mediated by mTORC1. It may act as a tumor suppressor. Relationships
between SDH and TMEM127 poorly known.
Cancer-related alterations:
Pheochromocytomas (PCC) and paragangliomas
(PGL) are rare, usually benign tumors of the sympathetic or parasympathetic
paraganglia. Pheochromocytoma is the tumor of the main sympathetic paraganglia,
which is the adrenal medulla. The sympathetic paraganglioma secretes
catecholamine while the parasympathetic do not. Both of them originate from
neural crest cells and share similar mechanisms of tumor development. The same
genetic alteration may predispose to the development of sympathetic and
parasympathetic paraganglioma. Up to 35% of these tumors may be hereditary;
they are associated with germline mutations in genes encoding subunits of the
succinate dehydrogenase (SDH) enzyme complex in the context of the familial PGL
syndromes, PGL1, 3 and 4 caused by mutations in the SDHD,SDHC and SDHB genes,
respectively. Another familial PGL syndrome, PGL2, which is currently
exclusively associated with head and neck paragangliomas, is caused by
mutations in SDHAF2. Recently mutations were found in the SDHA subunit in a
limited number of patients with PGL and/or PCC. Another gene found to
predispose to PGL and/or PCC when mutated is TMEM127.
Less frequently, mutations in the genes
responsible for Von Hippel Lindau disease (VHL), multiple endocrine neoplasia
type 2 (MEN2), and neurofibromatosis type 1 (NF1) are also found in patients
with hereditary PCC and PGL.
The
SDHB, SDHC and SDHD gene mutations (but not SDHA) can also be found in patients
with PGL and/or PCC and gastrointestinal stromal tumors (GISTs), also known as
the Carney-Stratakis syndrome; SDHB mutations, in particular, may also
predispose to thyroid and renal cancer, and possibly other tumors.
Mitochondrial dysfunction due to SDHx
mutations have been linked to tumorigenesis by upregulation of hypoxic and
angiogenesis pathways, apoptosis resistance and developmental culling of
neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to
more or less distinct clinical phenotypes. SDHB mutations mainly predispose to
extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant
potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are
typically associated with multifocal HNPGL and usually benign adrenal and
extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most
abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or
norepinephrine and dopamine.
References:
Recent advances in the genetics of
SDH-related paraganglioma and pheochromocytoma. Hensen EF, Bayley JP. Fam
Cancer. 2011 Jun;10(2):355-63.
SDHA is a tumor suppressor gene causing
paraganglioma. Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F,
Jouanno E, Jeunemaitre X, Bénit P, Tzagoloff A, Rustin P, Bertherat J, Favier
J, Gimenez-Roqueplo AP. Hum Mol Genet. 2010 Aug 1;19(15):3011-20.
Hereditary Paraganglioma-Pheochromocytoma Syndromes.
Klein RD, Lloyd RV, Young WF. In: Pagon RA, Bird TD, Dolan CR, Stephens
K, editors. SourceGeneReviews [Internet]. Seattle (WA): University of
Washington, Seattle; 1993-.2008 May 21 [updated 2009 Sep 03].
The triad of paragangliomas, gastric
stromal tumours and pulmonary chondromas (Carney triad), and the dyad of
paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome):
molecular genetics and clinical implications. Stratakis CA,
Carney JA. J Intern Med. 2009 Jul;266(1):43-52.
