Familial thrombocytosis caused by the novel germ‐line mutation p.Pro106Leu in the MPL gene

Abstract

Summary Familial thrombosis (FT) has been described as a rare autosomal‐dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3·3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0·001, Fisher’s exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal‐recessive with possible mild heterozygote manifestation rather than autosomal‐dominant with high penetrance as usually seen in FT.

Acknowledgments / The Authors

“…22 Two germ line MPL mutations have been so far reported: the MPL Baltimore polymorphism 23 and the MPL p.Pro106Leu mutation. 24 Both these mutations involve the extracellular domain of MPL, affecting its binding ability to thrombopoietin. In fact, these patients have high serum levels of thrombopoietin, 23 probably because of decreased thrombopoietin clearance.…”

Clinical utility gene card for: Hereditary thrombocythemia

“…5 Hereditary thrombocythemia cases with associated MPL alterations (THCYT2) have been described in Japan, 10 Italy 11,12 North America (African Americans) 8 and Arabia. 9 Regional/ethnic association is known for MPL K39N (B7% of African Americans are heterozygous for MPL K39N, n ¼ 12/161) and MPL P106L (B5% in Arab population, n ¼ 11/213; B1% are homozygous and B4% are heterozygous for MPL P106L). The frequency of MPL K39N in other American ethnics is 0% (Caucasian, n ¼ 0/250; Hispanic, n ¼ 0/40; Asian, n ¼ 0/39).…”

“…The frequency of MPL P106L in German individuals is 0% (n ¼ 0/193). 8,9 As yet, MPL S505N has not been systematically evaluated regarding regional/ethnic association.…”

“…9 Autosomal-dominant THCYT1, non-MPL P106L THCYT2 and THCYT3: 100% in heterozygously and homozygously mutated cases. 20,21 2.6 Negative clinical predictive value (probability of not developing the disease if the test is negative) Assume an increased risk based on family history for a non-affected person.…”

Hereditary myeloproliferative disorders

“…mutations in the N-terminal region of the extracellular domain of Mpl protein, MPL-K39N (also called MPL-Baltimore), 27 and MPL-P106L, which is associated with a co-dominant transmission of thrombocytosis with elevated serum thrombopoietin levels in families of Arabic descent. 28 The experience from the studies on MPL and THPO will undoubtedly help to design the case-control studies that can address the most interesting issues, such as severity of myelofibrosis, progression to leukemia, but also therapeutic decisions, such as which patients with inherited MPL and THPO mutations should receive low dose aspirin. ) acute lymphoblastic leukemia (ALL) is a relatively uncommon disease.…”