Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Mar 2;5(3):237-250.
doi: 10.1002/mgg3.279. eCollection 2017 May.

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

Ruth T Casey  1   2 , David B Ascher  3   4 , Eleanor Rattenberry  5 , Louise Izatt  6 , Katrina A Andrews  1 , Helen L Simpson  2 , Benjamen Challis  2 , Soo-Mi Park  1 , Venkata R Bulusu  7 , Fiona Lalloo  8 , Douglas E V Pires  9 , Hannah West  1 , Graeme R Clark  1 , Philip S Smith  1 , James Whitworth  1 , Thomas G Papathomas  10 , Phillipe Taniere  11 , Rosina Savisaar  12 , Laurence D Hurst  12 , Emma R Woodward  5   8 , Eamonn R Maher  1
Affiliations

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity

Ruth T Casey et al. Mol Genet Genomic Med. .

Abstract

Purpose: To evaluate the role of germline SDHA mutation analysis by (1) comprehensive literature review, (2) description of novel germline SDHA mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.

Patients and methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of SDHA missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform. These structural predictions were correlated with the results of tumor studies and other bioinformatic predictions.

Results: Literature review revealed reports of 17 different germline SDHA variants in 47 affected individuals from 45 kindreds. A further 10 different variants in 15 previously unreported cases (seven novel variants in eight patients) were added from our UK series. In silico structural prediction studies of 11 candidate missense germline mutations suggested that most (63.7%) would destabilize the SDHA protomer, and that most (78.1%) rare SDHA missense variants present in a control data set (ESP6500) were also associated with impaired protein stability.

Conclusion: The clinical spectrum of SDHA-associated neoplasia differs from that of germline mutations in other SDH-subunits. The interpretation of the significance of novel SDHA missense substitutions is challenging. We recommend that multiple investigations (e.g. tumor studies, metabolomic profiling) should be performed to aid classification of rare missense variants before genetic testing results are used to influence clinical management.

Keywords: Pathogenesis; SDHA; variant.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Molecular depiction of the effect on protein caused by c.1873C>T (p.His625Tyr) SDHA mutation.
Figure 2
Figure 2
Molecular depiction of the effect on protein caused by c.923C>T (P.Thr308Met) SDHA mutation.
Figure 3
Figure 3
Modeling of mammalian alignment to detect domains of purifying selection using SDHA transcript.
See this image and copyright information in PMC

References

    1. Astuti, D. , Douglas F., Lennard T. W., Aligianis I. A., Woodward E. R., Evans D. G., et al. 2001a. Germline SDHD mutation in familial phaeochromocytoma. Lancet 357:1181–1182. - PubMed
    1. Astuti, D. , Latif F., Dallol A., Dahia P. L., Douglas F., George E., et al. 2001b. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69:49–54. - PMC - PubMed
    1. Baysal, B. E. , Ferrell R. E., Willett‐Brozick J. E., Lawrence E. C., Myssiorek D., Bosch A., et al. 2000. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851. - PubMed
    1. Baysal, B. E. , Lawrence E. C., and Ferrell R. E.. 2007. Sequence variation in human succinate dehydrogenase genes: evidence for long‐term balancing selection on SDHA. BMC Biol. 5:12. - PMC - PubMed
    1. Belinsky, M. G. , Rink L., Flieder D. B., Jahromi M. S., Schiffman J. D., Godwin A. K., et al. 2013a. Over‐expression of IGF1R and frequent mutational inactivation of SDHA in wild‐type sdhb‐negative gastrointestinal stromal tumors. Genes Chromosom. Cancer 52:214–224. - PMC - PubMed

LinkOut - more resources