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Heterogeneity in CAMT-MPL
Less severe courses (thrombocytopenia not detected at birth or onset of pancytopenia not in early childhood) were observed in patients with mutations p.Met8Arg, p.Asp295Tyr, p.Pro394Ser and missense mutations in exons 11 and 12 affecting the intracytoplasmic part of the receptor molecule (p.Leu524Arg, p.Pro581Leu, p.Leu594Trp). p.Met8Arg is the most N-terminal muta- tion in MPL described so far. The mutation is located in the signal peptide region of the MPL precursor protein and might affect signaling of the molecule as well as the function of this codon as a possible alternative translation initiation site. It was homozygously found in a patient from consanguineous parents first diagnosed with throm- bocytopenia at the age of 9 months.
The mutation p.Arg454Pro which is predicted to be benign by all applied prediction algorithms was homozy-
gously found in a patient presenting at the age of 2 years with a profound isolated hypomegakaryocytic thrombocy- topenia.
p.Arg102His is the third mutation affecting Arg102 in CAMT: p.Arg102Cys and p.Arg102Pro cause a severe phe- notype of CAMT in patients15 and disturb intracellular traf- ficking of the MPL protein27 although p.Arg102His as well as p.Arg102Pro are predicted to be benign by SIFT and PROVEAN algorithms (Table 2D).
* The nomenclature of sequence variants follows the recommendations of the Human Genome Variation Society (HGVS). A discription at the DNA level is provided in the Online Supplementary Table S2. Missense mutations are described at protein level, other mutations on DNA level (coding sequence). Amino acid substitutions are deduced from DNA sequencing results, the recom- mended parentheses have been omitted for better readability.
Table 1. Congenital amegakaryocytic thrombocytopenia patients included in this study.
patient ID
CAMT001 CAMT006 CAMT007 CAMT009 CAMT011
CAMT012 CAMT013 CAMT015 CAMT017 CAMT018 CAMT019 CAMT030 CAMT031 CAMT033
CAMT034 CAMT036 CAMT039
CAMT043 CAMT050 CAMT052 CAMT055 CAMT058
CAMT059 CAMT067
CAMT075 CAMT082
CAMT083 CAMT087 CAMT092
CAMT098
sex intron/exon
f E2 f E3 m E3 f E3 f E5 E3 m E3 f E3 f E3 f E2 f E2 f E2 m I1 f E3 f E3
I2 f E3 m E2 f E3 E3 f E3 f E4 f E8 m E5 m E4
E12 m E8
m E3 E3
m E3
m E3 I3
m E8 m E2 f I3 E9 m I1
CDS
c.127C>T
c.268C>T
c.305G>C
c.378delT
c.823C>A
c.305G>C
c.305G>C
c.235_236delCT
c.305G>C
c.127C>T
c.127C>T
c.127C>T
c.79+2T>A
c.378delT
c.378delT c.213-1G>A
c.378delT
c.127C>T
c.378delT
c.367C>T
c.304C>T
c.460T>C
c.1305G>C
c.770G>T
c.407C>T
c.1781T>G
c.1230G>A
c.305G>C c.311T>C
c.305G>C
c.305G>C c.391+5G>C
c.1305G>C
c.127C>T
c.391+5G>C
c.1378C>T
c.79+2T>A
c.404C>G
protein
p.Arg43Ter
p.Arg90Ter
p.Arg102Pro
p.Phe126LeufsTer5
p.Pro275Thr
p.Arg102Pro
p.Arg102Pro
p.Leu79GlufsTer84
p.Arg102Pro
p.Arg43Ter
p.Arg43Ter
p.Arg43Ter
p.Asp27fs
p.Phe126LeufsTer5
p.Phe126LeufsTer5 splicing defect
p.Phe126LeufsTer5
p.Arg43Ter
p.Phe126LeufsTer5
p.Arg123Ter
p.Arg102Cys
p.Trp154Arg
p.Trp435Cys
p.Arg257Leu
p.Pro136Leu
p.Leu594Trp
p.Trp410Ter
p.Arg102Pro p.Phe104Ser
p.Arg102Pro
p.Arg102Pro splicing defect
p.Trp435Cys
p.Arg43Ter
splicing defect
p.Gln460Ter
splicing defect p.Pro135Arg
patient ID
CAMT101 CAMT102 CAMT108
CAMT113
CAMT122 CAMT123 CAMT125 CAMT130
CAMT133 CAMT136 CAMT137
CAMT138 CAMT140 CAMT144
CAMT157 CAMT159 CAMT160 CAMT163 CAMT167 CAMT168 CAMT169
CAMT178
CAMT179
CAMT180 CAMT181
CAMT183
sex intron/exon
m E6 f E6 f E3
I11 f I2 I3
f E12 f E4 f E4 f I3
E5 f E8 m E9 f I3
E5 f E9 m E8 f E3 E4 m E4 f E1 m E3 f E9 f E5
m E11
m E3 E3
f E3 E4
f E4 E6
m E2
f E3 I9
f E4
CDS
c.883G>C
c.883G>C
c.378delT
c.1653delG
c.212+1G>A
c.391+5G>C
c.1742C>T
c.460T>C
c.407C>A
c.391+5G>C
c.769C>T
c.1180C>T
c.1361G>C
c.391+5G>C c.769C>T
c.1390A>G
c.1180C>T
c.304C>T
c.407C>T
c.506T>A
c.23T>G
c.235_236delCT
c.1431G>A
c.805T>C
c.1571T>G
c.305G>A
c.235_236delCT
c.305G>C
c.506T>A
c.407C>G c.944T>G
c.127C>T c.305G>C
c.1469-2A>T c.506T>A
protein
p.Asp295Tyr
p.Asp295Tyr
p.Phe126LeufsTer5
p.Lys553ArgfsX75
splicing defect
splicing defect
p.Pro581Leu
p.Trp154Arg
p.Pro136His
splicing defect
p.Arg257Cys
p.Pro394Ser
p.Arg454Pro
splicing defect p.Arg257Cys
p.Arg464Gly
p.Pro394Ser
p.Arg102Cys
p.Pro136Leu
p.Leu169His
p.Met8Arg
p.Leu79GlufsX84
p.Trp477Ter
p.Trp269Arg
p.Leu524Arg
p.Arg102His p.Leu79GlufsX84
p.Arg102Pro p.Leu169His
p.Pro136Arg p.Phe315Cys
p.Arg43Ter
p.Arg102Pro splicing defect
p.Leu169His
E4
Congenital amegakaryocytic thrombocytopenia (CAMT) patients included in this study. Patients are listed with MPL mutations (bold: novel mutations) and predicted effect on the MPL protein; f: female, m: male; ID: identifier; I: intron; E: exon; CDS: cod- ing DNA sequence.
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