MRPS22

MRPS22 encodes a critical component of the mitochondrial ribosome, which is required for the synthesis of proteins essential to cellular energy production. 

Mutations in this gene are linked to severe multisystem mitochondrial disorders such as Combined Oxidative Phosphorylation Deficiency 5 (COXPD5) and tissue-specific conditions like Primary Ovarian Insufficiency (POI), underscoring its broad clinical relevance in both pediatric and reproductive medicine.

What is MRPS22 (Mitochondrial Ribosomal Protein S22)?

MRPS22 is a nuclear gene that provides instructions for making mitochondrial ribosomal protein S22 (mS22). This protein is part of the 28S small subunit of the mitochondrial ribosome, which produces essential proteins within mitochondria.

Mitochondrial ribosomes (mitoribosomes) differ from those in the cell cytoplasm. They have a higher protein-to-RNA ratio and lack some components like 5S rRNA. 

MRPS22 is vital for the assembly and stability of the mitochondrial ribosome, which is required for producing proteins encoded by mitochondrial DNA. These proteins are essential for oxidative phosphorylation (OXPHOS)—the process cells use to produce energy (ATP).

Conditions Associated with MRPS22 Mutations

The following conditions have been associated with MRPS22 mutations:

Combined Oxidative Phosphorylation Deficiency 5 (COXPD5)

Combined Oxidative Phosphorylation Deficiency 5 (COXPD5) is a rare, autosomal recessive mitochondrial disorder caused by biallelic mutations in the MRPS22 gene.

It presents in the prenatal or neonatal period with severe hypotonia, lactic acidosis, congenital hyperammonemia, hypertrophic cardiomyopathy, and multisystem involvement, including neurologic, renal, and craniofacial abnormalities. Affected infants often have poor growth, metabolic crises, and early mortality. 

Genetic testing for MRPS22 variants confirms the diagnosis, often alongside evidence of impaired activity in mitochondrial respiratory chain complexes. 

Prognosis is poor, and management is supportive.

Primary Ovarian Insufficiency (POI)

Primary ovarian insufficiency (POI) is a condition characterized by ovarian dysfunction in women under age 40, typically presenting with ≥4–6 months of amenorrhea, elevated follicle-stimulating hormone (FSH), and low estradiol levels. Unlike menopause, POI involves intermittent and unpredictable ovarian activity and residual follicular function.

Etiologies include genetic mutations (e.g., FMR1 premutation, Turner syndrome), autoimmune diseases (e.g., Addison disease, Hashimoto thyroiditis), environmental toxins, and iatrogenic factors such as chemotherapy or oophorectomy. In over 90% of cases, the cause is idiopathic.

POI leads to infertility and long-term hypoestrogenism, increasing the risk of osteoporosis, cardiovascular disease, and mood disorders. 

Diagnosis requires exclusion of secondary causes of amenorrhea and confirmation with elevated FSH on two occasions, at least one month apart.

Management centers on hormone replacement therapy (HRT) to restore physiologic estrogen levels, protect bone and heart health, and alleviate vasomotor and genitourinary symptoms. 

Fertility preservation options are limited; oocyte donation remains the most effective strategy for conception.

When is MRPS22 Testing or Research Relevant?

MRPS22 testing may be relevant in the following scenarios:

Research Settings

MRPS22 mutations have been linked to several rare genetic disorders that affect mitochondrial function. These include:

• Combined Oxidative Phosphorylation Deficiency 5 (COXPD5): A multisystem mitochondrial disease.
• Primary Ovarian Insufficiency (POI): Premature loss of ovarian function.
• Hypertrophic Cardiomyopathy: Heart muscle thickening may occur in some mitochondrial disease cases.

Clinical Testing

Genetic testing for MRPS22 may be considered in patients with:

• Neonatal hypotonia, lactic acidosis, or metabolic crisis
• Unexplained cardiomyopathy or kidney tubulopathy
• Early-onset POI in 46,XX females without other syndromic features
• Family history consistent with autosomal recessive inheritance

Testing methods include sequencing, deletion/duplication analysis, and inclusion in mitochondrial disease or POI gene panels.

MRPS22 Genetic Testing: Test Procedure and Interpretation

Testing for MRPS22 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for MRPS22 genetic testing are considered to be without mutations that can alter the activity of the MRPS22 proteins.

What Do MRPS22 Mutations Mean?

MRPS22 mutations may have the following clinical significance:

Mitochondrial Dysfunction

Mutations in MRPS22 can prevent proper formation of mitochondrial ribosomes, leading to:

• Reduced mitochondrial protein synthesis
• Impaired function of respiratory chain complexes I, III, and IV
• Energy failure in tissues with high metabolic demands

Clinical Features Vary by Condition

• COXPD5: Presents in infancy with severe hypotonia, lactic acidosis, heart defects (e.g. hypertrophic cardiomyopathy), kidney dysfunction, and early death.
• POI (Ovarian Dysgenesis 7): Affects females with primary amenorrhea, delayed puberty, and underdeveloped ovaries or uterus, but often no other systemic symptoms.

Common Pathogenic Variants

• Frameshift: c.874_875del (p.Asp292fs)
• Splice-site: c.648+1G>T
• Missense: p.Arg170His, p.Ile253Thr, p.R202H
• Nonsense: p.Arg191Ter

Some POI-associated variants (e.g., p.R202H, p.R135Q) show tissue-specific effects without global energy failure, suggesting a specialized role in ovarian germ cell development.

What Does the Absence of an MRPS22 Mutation Mean?

A negative test result for MRPS22 does not rule out a mitochondrial or reproductive disorder. Many other genes are involved in mitochondrial translation and OXPHOS. Broader testing may be needed if clinical suspicion remains high.

Clinical Implications and Research Highlights

Clinical implications and research highlights may include:

Animal Models

• Mice lacking MRPS22 die before gastrulation, showing its critical role in early development.
• In fruit flies, MRPS22 deficiency in germ cells causes sterility.

Diagnostic Clues

• COXPD5: Dysmorphic features, corpus callosum hypoplasia, metabolic acidosis, elevated lactate.
• POI: Amenorrhea, small or absent ovaries, no syndromic findings.

Testing Recommendations

• Include MRPS22 in gene panels for mitochondrial disorders and idiopathic POI.
• Use molecular and functional studies (e.g., qPCR, protein rescue assays) when needed.

Clinician Summary

• Gene: MRPS22 (Mitochondrial Ribosomal Protein S22)
• Protein Role: Structural subunit of the 28S mitochondrial ribosome
• Location: Chromosome 3q23
• Associated Disorders:
  
  • Combined Oxidative Phosphorylation Deficiency 5 
  • Ovarian Dysgenesis 7 / Primary Ovarian Insufficiency 
• Inheritance Pattern: Autosomal recessive
• Common Clinical Features:
  
  • Hypotonia
  • Hypertrophic cardiomyopathy
  • Primary ovarian insufficiency (POI)
  • Developmental delay
• Clinical Utility:
  
  • Inclusion in diagnostic gene panels for suspected mitochondrial disorders
  • Evaluation in cases of idiopathic POI with autosomal recessive inheritance patterns

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