Molecular Studies of Diamond-Blackfan Anemia and - DiVA

66 Pages·2010·3.09 MB·English

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Faculty opponent Catharina Larsson, Professor, M.D.
Karolinska Institute
Stockholm, Sweden

Examining committee Helena Jernberg-Wiklund, Professor
Uppsala University
Uppsala, Sweden

Mikael Lindström, Associate Professor
Karolinska Institute
Stockholm, Sweden

Gunnar Schulte, Associate Professor
Karolinska Institute
Stockholm, Sweden

Chairman Larry Mansouri, Ph.D.
Uppsala University
Uppsala, Sweden

Supervisors Niklas Dahl, Professor, M.D
Jens Schuster, Ph.D.
Uppsala University
Uppsala, Sweden

List of Papers
This thesis is based on the following papers, which are referred to in the text
by their corresponding Roman numerals (I-IV).

I Fröjmark, AS., Badhai, J., Klar, J., Thuveson, M., Schuster, J.,
Dahl, N. (2009) Cooperative effect of ribosomal protein s19 and
Pim-1 kinase on murine c-Myc expression and myelo-
id/erythroid cellularity. Journal of Molecular Medicine,
88(1):39–46

II Badhai, J., Fröjmark, AS., Davey, E., Schuster, J., Dahl, N.
(2009) Ribosomal protein S19 and S24 insufficiency cause dis-
tinct cell cycle defects in Diamond-Blackfan anemia. Biochimi-
ca et Biophysica Acta - Molecular Basis of Disease,
1792(10):1036-42

III Schuster, J., Fröjmark, AS., Nilsson, P., Badhai, J., Virtanen,
A., Dahl, N. (2010) Ribosomal protein S19 binds to its own
mRNA with reduced affinity in Diamond-Blackfan anemia.
Blood cells, Molecules, and Diseases, 45(1):23-28

IV Fröjmark, AS., Schuster, J*., Entesarian, M*., Sobol, M., Na-
waz, S., Baig, SM., Klar, J., Dahl, N. Mutations in Frizzled 6
(FZD6) cause isolated autosomal recessive nail dysplasia.
Manuscript
*These authors contributed equally to the work.
Reprints were made with permission from the respective publishers.

Contents
Introduction ................................................................................................... 13
Genetic variation ...................................................................................... 13
Cell cycle .................................................................................................. 14
Apoptosis .................................................................................................. 15
Ribosomes and ribosomal biogenesis ....................................................... 17
Ribosomopathies ................................................................................. 19
Ribosomopathies and predisposition to malignancies ......................... 20
Hematopoiesis .......................................................................................... 20
Erythropoiesis ...................................................................................... 21
Diamond-Blackfan Anemia .......................................................................... 24
Diagnosis and clinical description ............................................................ 24
Treatment ................................................................................................. 24
Genetic studies ......................................................................................... 25
Genotype-phenotype correlation ......................................................... 25
Defective erythropoiesis in DBA ............................................................. 25
Hypothesizes and model systems ............................................................. 26
Ribosomal Stress Hypothesis .............................................................. 27
Translational Defect Hypothesis .......................................................... 27
Nail dysplasia ................................................................................................ 29
Embryonic development .......................................................................... 29
Limb development ............................................................................... 30
Nail development ................................................................................. 32
FZD/WNT signaling ................................................................................ 32
WNT/β-catenin pathway ...................................................................... 33
WNT/JNK pathway ............................................................................. 34
WNT/Ca2+ pathway ............................................................................. 35
Present investigations.................................................................................... 36
Aims ......................................................................................................... 36
Methods .................................................................................................... 36
Mouse models ...................................................................................... 38
Results and discussion .............................................................................. 38
Paper I. Cooperative effect of ribosomal protein s19 and Pim-1 kinase
on murine c-Myc expression and myeloid/erythroid cellularity. ......... 38
Paper II. Ribosomal protein S19 and S24 insufficiency cause distinct
cell cycle defects in Diamond-Blackfan anemia .................................. 41
Paper III. Ribosomal protein S19 binds to its own mRNA with reduced
affinity in Diamond-Blackfan anemia. ................................................ 42
Paper IV. Mutations in Frizzled 6 (FZD6) cause isolated autosomal
recessive nail dysplasia. ....................................................................... 43
Concluding remarks and future perspectives ................................................ 46
Diamond-Blackfan Anemia ...................................................................... 46
Nail dysplasia ........................................................................................... 49
Acknowledgements ....................................................................................... 51
References ..................................................................................................... 53