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. 2019 Sep;33(9):2324-2330.
doi: 10.1038/s41375-019-0452-6. Epub 2019 Apr 9.

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

Maroulio Pertesi  1   2 , Maxime Vallée  1 , Xiaomu Wei  3 , Maria V Revuelta  4 , Perrine Galia  5   6 , Delphine Demangel  5   6 , Javier Oliver  1   7 , Matthieu Foll  1 , Siwei Chen  3 , Emeline Perrial  8   9 , Laurent Garderet  10   11   12 , Jill Corre  13 , Xavier Leleu  14 , Eileen M Boyle  15 , Olivier Decaux  16   17   18 , Philippe Rodon  19 , Brigitte Kolb  20 , Borhane Slama  21 , Philippe Mineur  22 , Eric Voog  23 , Catherine Le Bris  24 , Jean Fontan  25 , Michel Maigre  26 , Marie Beaumont  27 , Isabelle Azais  28 , Hagay Sobol  29 , Marguerite Vignon  30 , Bruno Royer  30 , Aurore Perrot  31 , Jean-Gabriel Fuzibet  32 , Véronique Dorvaux  33 , Bruno Anglaret  34 , Pascale Cony-Makhoul  35 , Christian Berthou  36 , Florence Desquesnes  37 , Brigitte Pegourie  38 , Serge Leyvraz  39 , Laurent Mosser  40 , Nicole Frenkiel  41 , Karine Augeul-Meunier  42 , Isabelle Leduc  43 , Cécile Leyronnas  44 , Laurent Voillat  45 , Philippe Casassus  46 , Claire Mathiot  47 , Nathalie Cheron  48 , Etienne Paubelle  49 , Philippe Moreau  50 , Yves-Jean Bignon  51 , Bertrand Joly  52 , Pascal Bourquard  53 , Denis Caillot  54 , Hervé Naman  55 , Sophie Rigaudeau  56 , Gérald Marit  57 , Margaret Macro  58 , Isabelle Lambrecht  59 , Manuel Cliquennois  60 , Laure Vincent  61 , Philippe Helias  62 , Hervé Avet-Loiseau  63 , Victor Moreno  64   65 , Rui Manuel Reis  66   67 , Judit Varkonyi  68 , Marcin Kruszewski  69 , Annette Juul Vangsted  70 , Artur Jurczyszyn  71 , Jan Maciej Zaucha  72 , Juan Sainz  73 , Malgorzata Krawczyk-Kulis  74 , Marzena Wątek  75   76 , Matteo Pelosini  77 , Elzbieta Iskierka-Jażdżewska  78 , Norbert Grząśko  79 , Joaquin Martinez-Lopez  80 , Andrés Jerez  81 , Daniele Campa  82 , Gabriele Buda  76 , Fabienne Lesueur  83 , Marek Dudziński  84 , Ramón García-Sanz  85 , Arnon Nagler  86 , Marcin Rymko  87 , Krzysztof Jamroziak  75 , Aleksandra Butrym  88 , Federico Canzian  89 , Ofure Obazee  89 , Björn Nilsson  2 , Robert J Klein  90 , Steven M Lipkin  4 , James D McKay  91 , Charles Dumontet  92   93   94   95
Affiliations

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

Maroulio Pertesi et al. Leukemia. 2019 Sep.
No abstract available

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
DIS3 variants in MM cases. a Pedigrees from families carrying a germline DIS3 variant. Available samples for screening are marked with a “+” symbol. Families A and C carry the p.*959Glnext*14 (c.2875T>C) stop-loss variant. Family B carries the c.1755+1G>T splicing variant and family D carries the c.1883+1G>C splicing variant. The genotype of all screened individuals is shown on each pedigree. WT: wild type. b, c Schematic representation of identified germline and somatic variants in the distinct DIS3 protein domains. b Germline variants were identified through WES and targeted resequencing in families with reoccurrence of MM/MGUS as well as in a collection of sporadic MM cases (MMRF CoMMpass Study). The DIS3 variants discussed in the present study are depicted with a star on the upper part of the figure. c Somatic DIS3 variants were identified in sporadic MM cases from the MMRF CoMMpass Study. We observe that in contrast to the clustering of somatic DIS3 missense variants in the RNB and PIN domains, germline variants are scattered throughout the gene and consist of splicing, stop-loss and missense variants
Fig. 2
Fig. 2
DIS3 c.1755+1G>T splicing variant results in nonsense-mediated mRNA decay (NMD) and affects mRNA expression, while the c.2875C>T (p.*959Glnext*14) stop-loss variant affects protein levels. a LCLs from patients E18 and E28 (not shown) carrying the c.1755+1G>T splicing variant were cultured with and without puromycin. The chromatogram from treated cells (with puromycin) showed a mixture of the wild-type and mutant transcript lacking exon 13, which was not detected in the non-treated cells (without puromycin). Thus, the mutant transcript is degraded by NMD. b Box plot representing the relative DIS3 mRNA expression in c.1775+1G>A (n=2) and p.*959Glnext*14 (n = 1) carriers compared to non-carriers (n = 4). All reactions were performed in triplicates. c Western blot with an anti-DIS3 antibody was performed in LCLs from one p.*959Glnext*14 carrier and two wild-type individuals (anti-GAPDH antibody as internal control). The relative DIS3 expression in the p.*959Glnext*14 carrier was reduced by 50% compared to non-carriers, suggesting that the mutant allele is translated but degraded shortly after
See this image and copyright information in PMC

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