Exome Sequencing Identifies MPL As a Causative Gene in Familial Aplastic Anemia

Overview

Journal Haematologica

Specialty Hematology

Date 2011 Dec 20

PMID 22180433

Citations 20

Authors

Amanda J Walne

Arran Dokal

Vincent Plagnol

Richard Beswick

Michael Kirwan

Josu de la Fuente

Tom Vulliamy

Inderjeet Dokal

Affiliations

Soon will be listed here.

Abstract

The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis.

Citing Articles

Whole Exome Sequencing of Adult Indians with Apparently Acquired Aplastic Anaemia: Initial Experience at Tertiary Care Hospital.

Mehta S, Medicherla K, Gulati S, Sharma N, Parveen R, Mishra A Diseases. 2024; 12(9).

PMID: 39329894 PMC: 11430975. DOI: 10.3390/diseases12090225.

Studying the pathogenicity of 26 variants characterized in the first molecular analyses of Egyptian aplastic anemia patients.

Sokkar M, Hamdy M, Erian P, Mosaad R, Elaraby N, Taher M J Genet Eng Biotechnol. 2023; 21(1):149.

PMID: 38017244 PMC: 10684839. DOI: 10.1186/s43141-023-00585-8.

Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management.

Stockklausner C, Duffert C, Cario H, Knofler R, Streif W, Kulozik A Ann Hematol. 2021; 100(7):1647-1665.

PMID: 33712866 PMC: 8195939. DOI: 10.1007/s00277-021-04485-0.

CAMT-MPL: congenital amegakaryocytic thrombocytopenia caused by MPL mutations - heterogeneity of a monogenic disorder - a comprehensive analysis of 56 patients.

Germeshausen M, Ballmaier M Haematologica. 2020; 106(9):2439-2448.

PMID: 32703794 PMC: 8409039. DOI: 10.3324/haematol.2020.257972.

The Pathophysiology of Acquired Aplastic Anemia: Current Concepts Revisited.

Schoettler M, Nathan D Hematol Oncol Clin North Am. 2018; 32(4):581-594.

PMID: 30047412 PMC: 6538304. DOI: 10.1016/j.hoc.2018.03.001.

References

Young N, Scheinberg P, Calado R . Aplastic anemia. Curr Opin Hematol. 2008; 15(3):162-8. PMC: 3410534. DOI: 10.1097/MOH.0b013e3282fa7470. View

Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A . c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood. 2001; 97(1):139-46. DOI: 10.1182/blood.v97.1.139. View

Ballmaier M, Germeshausen M . Advances in the understanding of congenital amegakaryocytic thrombocytopenia. Br J Haematol. 2009; 146(1):3-16. DOI: 10.1111/j.1365-2141.2009.07706.x. View

Marrone A, Sokhal P, Walne A, Beswick R, Kirwan M, Killick S . Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations. Haematologica. 2007; 92(8):1013-20. PMC: 2892775. DOI: 10.3324/haematol.11407. View

Mardis E . Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet. 2008; 9:387-402. DOI: 10.1146/annurev.genom.9.081307.164359. View

Savoia A, Dufour C, Locatelli F, Noris P, Ambaglio C, Rosti V . Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations. Haematologica. 2007; 92(9):1186-93. DOI: 10.3324/haematol.11425. View

Germeshausen M, Ballmaier M, Welte K . MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease. Hum Mutat. 2006; 27(3):296. DOI: 10.1002/humu.9415. View

Lander E, Botstein D . Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987; 236(4808):1567-70. DOI: 10.1126/science.2884728. View

Yamaguchi H, Calado R, Ly H, Kajigaya S, Baerlocher G, Chanock S . Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005; 352(14):1413-24. DOI: 10.1056/NEJMoa042980. View

10.

Chou F, Mulloy J . The thrombopoietin/MPL pathway in hematopoiesis and leukemogenesis. J Cell Biochem. 2011; 112(6):1491-8. DOI: 10.1002/jcb.23089. View

11.

Ball S, Gibson F, Rizzo S, Tooze J, Marsh J, Gordon-Smith E . Progressive telomere shortening in aplastic anemia. Blood. 1998; 91(10):3582-92. View

12.

Kuhlenbaumer G, Hullmann J, Appenzeller S . Novel genomic techniques open new avenues in the analysis of monogenic disorders. Hum Mutat. 2011; 32(2):144-51. DOI: 10.1002/humu.21400. View

13.

Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, GOOD R . Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A. 1999; 96(6):3132-6. PMC: 15907. DOI: 10.1073/pnas.96.6.3132. View

14.

Geddis A . Congenital amegakaryocytic thrombocytopenia. Pediatr Blood Cancer. 2011; 57(2):199-203. DOI: 10.1002/pbc.22927. View

15.

Walne A, Vulliamy T, Beswick R, Kirwan M, Dokal I . Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum Mol Genet. 2010; 19(22):4453-61. PMC: 2957322. DOI: 10.1093/hmg/ddq371. View

16.

Cawthon R . Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009; 37(3):e21. PMC: 2647324. DOI: 10.1093/nar/gkn1027. View

17.

Knight S, Vulliamy T, Heiss N, Matthijs G, Devriendt K, Connor J . 1.4 Mb candidate gene region for X linked dyskeratosis congenita defined by combined haplotype and X chromosome inactivation analysis. J Med Genet. 1998; 35(12):993-6. PMC: 1051510. DOI: 10.1136/jmg.35.12.993. View

18.

Al-Qahtani F . Congenital amegakaryocytic thrombocytopenia: a brief review of the literature. Clin Med Insights Pathol. 2010; 3:25-30. PMC: 2999995. DOI: 10.4137/cpath.s4972. View

19.

Dokal I, Vulliamy T . Inherited bone marrow failure syndromes. Haematologica. 2010; 95(8):1236-40. PMC: 2913069. DOI: 10.3324/haematol.2010.025619. View

20.

Kaushansky K . Molecular mechanisms of thrombopoietin signaling. J Thromb Haemost. 2009; 7 Suppl 1:235-8. DOI: 10.1111/j.1538-7836.2009.03419.x. View