Disorders of Ribosomal Proteins and Related Hematologic Diseases

Introduction to Ribosomopathies

Ribosomopathies refer to diseases caused by defects in ribosomal constituents or impaired ribosome biogenesis. Abnormal ribosomal function greatly increases the risk of malignancy in humans. The p53 pathway can be activated by defects in ribosome biosynthesis and serves as a key mediator of many clinical features of ribosomal diseases. Therefore, mechanistic studies of selective abnormalities in ribosome biogenesis are expected to lead to new therapeutic strategies for these diseases.

Fig. 1 A simplified schematic of ribosome biogenesis in human cells.¹

• Diamond-Blackfan Anemia (DBA)

Diamond-Blackfan anemia (DBA) is congenital aplastic anemia characterized by anemia, macrocytosis, elevated erythrocyte adenosine deaminase levels, decreased reticulocytes, and decreased erythroid precursors in the bone marrow of normal cells. Current treatments include steroids and chronic blood transfusions, as well as bone marrow transplants.

Studies have shown that mutations in RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A can be found in DBA patients. In addition, RPS7, RPL36, RPS15, and RPS27A were also considered candidate mutations.

• 5q−Syndrome

5q−syndrome is an independent subtype of myelodysplastic syndrome (MDS) characterized by severe macrocytic anemia, elevated platelets, and low-segmented micromegakaryocytes, as well as relatively low rates of acute myeloid leukemia (AML) progression. RPS14 has been identified as a 5q-syndrome gene and haploinsufficiency of RPS14 has been demonstrated in patient samples. Furthermore, RPS14 deficiency results in blocked 18S rRNA processing and 40S ribosomal subunit formation.

• Shwachman-Diamond Syndrome

First reported in 1964, Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disease characterized by ineffective hematopoiesis, exocrine pancreatic insufficiency, and an increased risk of leukemia. Studies have shown that biallelic mutations in SBDS can be observed in approximately 90% of SDS patients. Although the structure and function of SBDS are unknown, SBDS has been shown to play an important role in stabilizing the mitotic spindle as well as in ribosome biogenesis.

• Dyskeratosis Congenita (DC)

Dyskeratosis congenita is a rare genetic form of bone marrow failure and stem cell transplantation is the only treatment option. In a generation, DC patients tend to have a higher risk of developing leukemia, solid tumors, and pulmonary fibrosis. Studies have shown that TERC mutations can often be found in DC patients and that telomeres play an important role in the pathogenesis of DC.

• Cartilage Hair Hypoplasia (CHH)

Cartilage hair hypoplasia (CHH) is short-limbed dwarfism caused by skeletal dysplasia and stem cell transplantation is the only treatment option. In 2001, scientists identified mutations in the untranslated RMRP gene as the cause of this pleiotropic disease. Various RMRP mutations may lead to abnormal ribosome assembly, telomere dysfunction, and altered cyclin B2 levels. In addition, mutations in RMRP are also associated with dysgenesis

• Treacher Collins Syndrome (TCS)

Treacher collins syndrome (TCS) is an autosomal dominant disorder. TCOF1, which encodes a protein known as treacle, has been identified as the gene responsible for TCS. Treacle is an essential component of the pre-ribosomal ribonucleoprotein (pre-RNP) complex, which is essential for the transcription of ribosomal DNA. Studies have shown that TCOF1 haploinsufficiency results in reduced ribosome production and eventual TCS development.

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Reference

1. Danilova, Nadia, and Hanna T. Gazda. "Ribosomopathies: how a common root can cause a tree of pathologies." Disease models & mechanisms 8.9 (2015): 1013-1026.