SRD5A3-CDG

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SRD5A3-CDG
Other namesCDG syndrome type Iq, CDG-Iq, CDG1Q or Congenital disorder of Glycosylation type 1q
SRD5A3 gene.png
SRD5A3 gene
Specialty Medical genetics
CausesMutation in the steroid 5 alpha reductase type 3 gene
FrequencyUltra rare

SRD5A3-CDG (also known as CDG syndrome type Iq, CDG-Iq, CDG1Q or Congenital disorder of glycosylation type 1q) is a rare, non X-linked congenital disorder of glycosylation (CDG) [1] due to a mutation in the steroid 5 alpha reductase type 3 gene. It is one of over 150 documented types of Congenital disorders of Glycosylation. [2] Like many other CDGs, SRD5A3 is ultra-rare, with around 38 documented cases in the world. [3]

Contents

It is an inheritable autosomal recessive disorder that causes developmental delays and problems with vision. The gene is located at 4q12, which is the long (q) arm of chromosome 4 at position 12. [4]

Presentation

SRD5A3-CDG is characterized by a highly variable phenotype. [5] Typical clinical manifestations include:

Less common manifestations may include:

Molecular mechanism

The protein encoded by the SRD5A3 gene is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. [7]

This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Dolichol is a key building block in the body's glycosylation process. [8] Typically, the dolichol generated is further modified into dolichol-linked oligosaccharide (DLO) by the addition of phosphates and sugars. Complex sugar molecules get added to DLO and are then transferred onto proteins. When insufficient DLO is produced in the body, many proteins are inadequately glycosylated.

Both glycosylation defects and an accumulation of polyprenol have been observed in SRD5A3-CDG patients and mouse models, and it is not currently known whether the disease is caused due to incorrect glycosylation, polyprenol accumulation, or a combination of the two.

Diagnosis

Confirmation of clinical diagnosis for SRD5A3-CDG requires genetic testing and gene sequencing to identify deleterious mutations in the SRD5A3 gene. Other diagnostic tools include Isoelectrofocusing of Transferrin (TIEF), an assay from transferrin levels in blood, to screen for N-glycosylation defects [9] which occur in CDGs. A CDG blood analysis test using mass spectrometry technology is also available.

As SRD5A3-CDG is also an inheritable disorder, [10] parental genetic testing can indicate if one or both of the parents are carriers of the faulty gene. The gene is recessive in nature, so if both parents are carriers of the condition, there is a 25% chance that the offspring will have SRD5A3-CDG.

Treatment

At present, there is no available treatment for SRD5A3-CDG. However, the disorder can be managed and some of the symptoms can be treated. [11] Some eye problems that manifest with SRD5A3-CDG can be surgically corrected and coagulation disorders may be treated.

The quality of life is mainly determined by the nature and the degree of the brain and eye involvement. Ongoing care and management for individuals with SRD5A3-CDG typically includes a combination of physical therapy (to alleviate issues pertaining to reduced muscle tone, mobility, etc.), occupational therapy (for vision and speech impairments) and palliative measures, where needed.

When a genetic risk or anomaly is identified, parents may have access to counselling to prepare them for any special needs their child may have and approaches on managing their condition as they grow.

Documented cases

SRD5A3-CDG is an ultra-rare disorder with a frequency of less than 1 in 10 million. [12] As of 2018, there were at least 38 reported cases of SRD5A3-CDG from 26 different families. While the exact number of patients worldwide is unknown, most recorded cases so far have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico and Turkey. [13]

Research

SRD5A3-CDG is caused by a single-gene mutation, which makes it an attractive candidate for gene therapy. However, due to the extreme rarity of the disorder, research around it has been limited.

Research has predominantly been focused on two types of research models: Cell-based models and model organisms. [14]

Common cell-based models include patient cells such as fibroblast cells derived from skin samples (patient-derived fibroblasts [PDFs]), induced pluripotent stem cells (iPSCs) created by reprogramming fibroblasts, and specialized cells, such as neurons derived from stem cell differentiation. Patient-derived cell models are important preclinical model systems as they contain the same genome and mutation(s) as the patient, allowing researchers to assess potential therapies for individual patients early on in the drug development process. For SRD5A3-CDG, patient-derived cell models could be crucial in understanding the impact of polyprenol reductase enzyme deficiency and be used to investigate various treatment options such as dietary supplementation, novel or repurposed drugs and gene therapy.

Model organisms like worms, zebrafish and mice have been genetically modified to study the impact of several mutations, including those in the SRD5A3 gene. Researchers in the United States and France have been working on genetically modified mice that have SRD5A3 mutations limited to the cerebellum region of their brain. [15] These mice are viable, show CDG symptoms in the brain, and are part of planned studies for new experimental treatments.

See also

Related Research Articles

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<span class="mw-page-title-main">ALG6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">DPAGT1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ALG2</span> Protein-coding gene in the species Homo sapiens

Alpha-1,3/1,6-mannosyltransferase ALG2 is an enzyme that is encoded by the ALG2 gene. Mutations in the human gene are associated with congenital defects in glycosylation The protein encoded by the ALG2 gene belongs to two classes of enzymes: GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase and GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase.

<span class="mw-page-title-main">B4GALT7</span> Protein-coding gene in the species Homo sapiens

Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.

<span class="mw-page-title-main">ALG8</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">DPM1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MPDU1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ALG12</span> Enzyme-coding gene in humans

Dolichyl-P-Man:Man(7)GlcNAc(2)-PP-dolichyl-alpha-1,6-mannosyltransferase is an enzyme that in humans is encoded by the ALG12 gene.

<span class="mw-page-title-main">Dehydrodolichyl diphosphate synthase</span> Enzyme found in humans

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<span class="mw-page-title-main">Congenital disorder of glycosylation type IIc</span> Medical condition

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<span class="mw-page-title-main">SRD5A3</span> Protein-coding gene in the species Homo sapiens

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Polyprenol reductase (EC 1.3.1.94, SRD5A3 (gene), DFG10 (gene)) is an enzyme with systematic name ditrans,polycis-dolichol:NADP+ 2,3-oxidoreductase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">PMM2 deficiency</span> Medical condition

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ALG1-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ALG1. The first cases of ALG1-CDG were described in 2004, and the causative gene was identified at the same time. This disorder was originally designated CDG-IK, under earlier nomenclature for congenital disorders of glycosylation. Clinically, individuals with ALG1-CDG have developmental delay, hypotonia, seizures and microcephaly. Fewer than 60 cases of ALG1-CDG have been confirmed in published literature. ALG1-CDG can be suspected based on clinical findings, and abnormal serum transferrin glycosylation test results. Confirmation of the diagnosis can be performed based on sequence analysis of ALG1. The analysis of ALG1 is complicated by the presence of a pseudogene. There are no specific treatments for ALG1-CDG, and most care consists of managing symptoms.

<span class="mw-page-title-main">SLC35A1-CDG</span> Medical condition

SLC35A1-CDG is a rare inherited disorder that mainly affects the vascular systems of the body. It forms part of a large group of disorders called congenital disorders of glycosylation. It is caused by mutations in the SLC35A1 gene, located in the sixth chromosome.

References

  1. ↑ "SRD5A3-CDG (CDG-Iq)". NIH Rare Diseases. US Department of Health and Human Services. Retrieved 9 October 2020.
  2. ↑ "CDG List" (PDF). CanadaCDG.com. Retrieved 9 October 2020.
  3. ↑ Jaeken, Jaak; Lefeber, Dirk (18 May 2020). "SRD5A3 defective congenital disorder of glycosylation: clinical utility gene card". European Journal of Human Genetics. 28 (9): 1297–1300. doi:10.1038/s41431-020-0647-3. PMC   7609305 . PMID   32424323.
  4. ↑ "Chromosome 4: Medline Plus Genetics". Medline Plus. US National Library of Science. Retrieved 9 October 2020.
  5. ↑ "SRD5A3 CDG". Orpha.net. Retrieved 9 October 2020.
  6. ↑ Sparks, Susan; Krasnewich, Donna (1993). "Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview". NCBI NIH. GeneReviews. PMID   20301507 . Retrieved 9 October 2020.
  7. ↑ "SRD5A3 Gene". Gene Cards. Weizmann Institute of Science. Retrieved 9 October 2020.
  8. ↑ Cantagrel, Vincent; Lefeber, Dirk; Ng, Bobby; Guan, Ziqiang (23 July 2010). "SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder". Cell. 142 (2): 203–217. doi:10.1016/j.cell.2010.06.001. PMC   2940322 . PMID   20637498.
  9. ↑ Barba, Carmen; Darra, Francesca; Procopio, Raffaella (13 May 2016). "Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in infancy". Developmental Medicine and Child Neurology. 58 (10): 1085–1091. doi: 10.1111/dmcn.13141 . PMID   27172925. S2CID   9598189.
  10. ↑ "SRD5A3 CDG Symptoms, Diagnosis & Treatment". Cure SRD5A3. 30 August 2020. Retrieved 12 May 2021.
  11. ↑ "SRD5A3 CDG Symptoms, Diagnosis & Treatment". Cure SRD5A3. 30 August 2020. Retrieved 12 May 2021.
  12. ↑ "SRD5A3 CDG". Orpha.net. Retrieved 9 October 2020.
  13. ↑ Jaeken, Jaak; Lefeber, Dirk; Matthijs, Gert (18 May 2020). "SRD5A3 defective congenital disorder of glycosylation: clinical utility gene card". European Journal of Human Genetics. 28 (9): 1297–1300. doi:10.1038/s41431-020-0647-3. PMC   7609305 . PMID   32424323.
  14. ↑ "Disease Models". Cure SRD5A3. 30 August 2020. Retrieved 9 October 2020.
  15. ↑ Medina-Cano, Daniel; Ucunco, Ekin; Nyugen, Lam S (12 October 2012). "High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect". eLife. 7. doi: 10.7554/eLife.38309 . PMC   6185108 . PMID   30311906.
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