Immunodeficiency in cartilage‐hair hypoplasia: Pathogenesis, clinical course and management

Vakkilainen, Svetlana; Taskinen, Mervi; Mäkitie, Outi

doi:10.1111/sji.12913

Cited by 32 publications

(70 citation statements)

References 67 publications

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“…To overcome the challenges of working with pre-RNA from fibroblasts, we generated a cell line homozygous for the most common CHH-associated mutation, an A to G transition at position 71 on the current reference sequence (NBCI sequence NR_003051.3; Fig. S2A) (Vakkilainen et al ., 2020). Prior literature refers to this mutation as 70 AG based on previous reference sequences, and we use 70 AG for consistency.…”

Section: Resultsmentioning

confidence: 99%

“…Some aspects of the two disorders do overlap; for example, some CHH patients have bone marrow dysfunction similar to that seen in DBA (Chirnomas & Kupfer, 2013). However, other aspects are unique, notably the T cell dysfunction which is life-limiting in CHH but not a feature of DBA (Vakkilainen et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

“…CC-BY 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted March 29, 2021. ; https://doi.org/10.1101/2021.03.29.437572 doi: bioRxiv preprint 6 (Vakkilainen et al, 2020). Prior literature refers to this mutation as 70 AG based on previous reference sequences, and we use 70 AG for consistency.…”

Section: Mutations Associated With Cartilage Hair Hypoplasia Impair Pmentioning

confidence: 99%

“…RMRP mutations are associated with a spectrum of disorders presenting with skeletal dysplasia, abnormal hair and immune deficiency with impaired T-cell activation (reviewed in (Vakkilainen et al , 2020). The most common of these syndromes is called Cartilage Hair Hypoplasia (CHH).…”

Section: Introductionmentioning

confidence: 99%

“…The most common of these syndromes is called Cartilage Hair Hypoplasia (CHH). Patients with CHH have reduced life expectancy due to immune deficiency, but the mechanism underlying this problem is not understood (Vakkilainen et al ., 2020). Clinically, patients often experience recurrent infections, and also have a higher incidence of auto-immunity and cancer.…”

Section: Introductionmentioning

confidence: 99%

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A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

Robertson

Shchepachev

Wright

et al. 2021

Preprint

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Mutations in the human RMRP gene cause Cartilage Hair Hypoplasia (CHH), an autosomal recessive disorder characterized by skeletal abnormalities and impaired T cell activation. RMRP encodes a non-coding RNA, which forms the core of the RNase MRP ribonucleoprotein complex. In budding yeast, RMRP cleaves a specific site in the pre-ribosomal RNA (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption of RMRP in human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations in RMRP impair mouse T cell activation and delay pre-rRNA processing. Analysis of pre-rRNA processing in patient-derived human fibroblasts with CHH-linked mutations showed a similar pattern of processing delay. Human cells engineered with the most common CHH mutation (70AG in RMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70AG mutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy, and the first human disorder of rRNA processing to be described.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mutations Associated With Cartilage Hair Hypoplasia Impair Pmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

Robertson

Shchepachev

Wright

et al. 2021

Preprint

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Organ‐based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians

Mohammadi

Yadegar

Mardani

et al. 2023

Immunity Inflam & Disease

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Inborn errors of immunity (IEI) comprise a group of about 490 genetic disorders that lead to aberrant functioning or the development of distinct immune system components. So far, a broad spectrum of IEI‐related manifestations has been noted in the literature. Due to overlapping signs and symptoms of IEI, physicians face challenges in appropriately diagnosing and managing affected individuals. The last decade has witnesses improving in the molecular diagnosis of IEI patients. As a result, it can be the mainstay of diagnostic algorithms, prognosis, and possibly therapeutic interventions in patients with IEI. Furthermore, reviewing IEI clinical complications demonstrates that the manifestations and severity of the symptoms depend on the involved gene that causes the disease and its penetrance. Although several diagnostic criteria have been used for IEI, not every patient can be explored in the same way. As a result of the failure to consider IEI diagnosis and the variety of diagnostic capabilities and laboratory facilities in different regions, undiagnosed patients are increasing. On the other hand, early diagnosis is an almost essential element in improving the quality of life in IEI patients. Since there is no appropriate guideline for IEI diagnosis in different organs, focusing on the clues in the patient's chief complaint and physical exams can help physicians narrow their differential diagnosis. This article aims to provide a practical guide for IEI diagnosis based on the involved organ. We hope to assist clinicians in keeping IEI diagnosis in mind and minimizing possible related complications due to delayed diagnosis.

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Analyzing the role of ferroptosis in ribosome‐related bone marrow failure disorders: From pathophysiology to potential pharmacological exploitation

Papadimitriou‐Tsantarliotou,

Avgeros,

Konstantinidou

et al. 2024

IUBMB Life

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Within the last decade, the scientific community has witnessed the importance of ferroptosis as a novel cascade of molecular events leading to cellular decisions of death distinct from apoptosis and other known forms of cell death. Notably, such non‐ apoptotic and iron‐dependent regulated cell death has been found to be intricately linked to several physiological processes as well as to the pathogenesis of various diseases. To this end, recent data support the notion that a potential molecular connection between ferroptosis and inherited bone marrow failure (IBMF) in individuals with ribosomopathies may exist. In this review, we suggest that in ribosome‐related IBMFs the identified mutations in ribosomal proteins lead to changes in the ribosome composition of the hematopoietic progenitors, changes that seem to affect ribosomal function, thus enhancing the expression of some mRNAs subgroups while reducing the expression of others. These events lead to an imbalance inside the cell as some molecular pathways are promoted while others are inhibited. This disturbance is accompanied by ROS production and lipid peroxidation, while an additional finding in most of them is iron accumulation. Once lipid peroxidation and iron accumulation are the two main characteristics of ferroptosis, it is possible that this mechanism plays a key role in the manifestation of IBMF in this type of disease. If this molecular mechanism is further confirmed, new pharmacological targets such as ferroptosis inhibitors that are already exploited for the treatment of other diseases, could be utilized to improve the treatment of ribosomopathies.

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Immunodeficiency in cartilage‐hair hypoplasia: Pathogenesis, clinical course and management

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 32 publications

References 67 publications

A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis

Organ‐based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians

Analyzing the role of ferroptosis in ribosome‐related bone marrow failure disorders: From pathophysiology to potential pharmacological exploitation

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