DGCR6L Human
Description
Genomic Context and Evolution
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Gene Duplication: DGCR6L arose from a duplication event of the ancestral DGCR6 locus. This duplication predates the divergence of Catarrhines (Old World monkeys) and Platyrrhines (New World monkeys), occurring at least 12–35 million years ago .
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Structural Features:
Table 1: Comparative Features of DGCR6 and DGCR6L
| Feature | DGCR6 | DGCR6L |
|---|---|---|
| Amino Acid Identity | 97% identical to DGCR6L | 97% identical to DGCR6 |
| Exons | 5 | 5 |
| Evolutionary Age | Ancestral gene | Duplicated ~12–35 mya |
Tissue Distribution
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Widely expressed in fetal and adult tissues, with highest levels in liver, heart, and skeletal muscle .
Functional Insights
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Neural Crest Development: Implicated in neural crest cell migration during pharyngeal arch formation, a process disrupted in DGS .
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Cancer Biology:
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Psychopathology:
DiGeorge/VCFS Syndromes
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Both DGCR6 and DGCR6L are deleted in >90% of 22q11DS cases .
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Reduced gene dosage may contribute to developmental defects in pharyngeal organs .
Methylation and Variability
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Promoter Methylation:
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Expression Variability: DGCR6 expression is more variable in 22q11DS patients than controls (Levene’s test: F = 7.68, P < 0.05) .
Key Studies
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Functional Redundancy: Both DGCR6 and DGCR6L are retained evolutionarily, suggesting non-redundant roles in development .
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Psychopathological Links: Lower DGCR6 expression in 22q11DS patients correlates with anxiety disorders, independent of parental origin .
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Cancer Mechanisms: DGCR6L-PAK4 interaction promotes LIMK1 activation, enhancing cancer cell migration .
Product Specs
Q&A
What is DGCR6L and where is it located in the human genome?
DGCR6L is a functional paralog of DGCR6 located on chromosome 22q11 within a low copy repeat termed sc11.1b. The gene encodes a putative protein with sequence similarity to gonadal (gdl), a Drosophila melanogaster gene of unknown function . The putative initiator methionine is positioned similarly to mouse and chicken orthologs, though further upstream than originally described . DGCR6L is frequently deleted in patients with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) as it maps adjacent to the low copy repeats (LCR22) that mediate the deletions associated with this syndrome .
How does DGCR6L differ structurally and functionally from DGCR6?
DGCR6L encodes a highly homologous, functional copy of DGCR6, with some base changes resulting in amino acid differences . While DGCR6 is located within the low copy repeat sc11.1a, DGCR6L resides in the duplicate locus sc11.1b . A notable structural difference is that a full-length HERV-K provirus integrated into the sc11.1a locus (containing DGCR6) after the divergence of chimpanzees and humans . Functionally, both genes appear to be widely expressed in fetal and adult tissues, suggesting overlapping but potentially distinct functions .
What is known about the evolutionary history of DGCR6L?
Evolutionary studies using FISH mapping in different ape species combined with sequence analysis of DGCR6 in various primate species indicate that the duplication event that created DGCR6L is at least 12 million years old . This duplication may date back to before the divergence of Catarrhines from Platyrrhines, approximately 35 million years ago . The long-term preservation of both functional copies suggests selective evolutionary pressure for their maintenance, indicating important biological functions for both genes .
How is DGCR6L expression regulated and what patterns are observed?
Both DGCR6 and DGCR6L are widely expressed in fetal and adult tissues, but their expression levels in 22q11.2 deletion syndrome patients show extreme variability . Surprisingly, some individuals with 22q11.2 deletions actually exhibit much higher levels of DGCR6 compared to normal controls . This variability appears to be epigenetically determined, as there is no evidence of maternal or paternal imprinting . The chicken ortholog of DGCR6 shows an embryonic expression pattern that is initially broad but becomes gradually restricted to neural crest cell derivatives of the cardiovasculature .
What is the association between DGCR6L and DiGeorge syndrome/22q11.2 deletion syndrome?
DGCR6L is typically deleted in patients with 22q11.2 deletion syndrome, which is characterized by congenital heart defects, thymic hypoplasia, hypoparathyroidism, and distinctive facial features . The majority of individuals with this syndrome have a 3 Mb deletion on chromosome 22, leading to haploinsufficiency of approximately 106 genes, including DGCR6L . Studies suggest that DGCR6 (and by extension, potentially DGCR6L) may influence neural crest cell migration, which is critical for the development of structures affected in DiGeorge syndrome .
What methodological approaches are most effective for studying DGCR6L expression and function?
| Methodology | Application to DGCR6L Research | Advantages | Limitations |
|---|---|---|---|
| Genomic Sequencing | Identifying gene structure and variants | High resolution of sequence elements | Difficulty distinguishing from DGCR6 due to homology |
| qPCR/RNA-seq | Expression profiling across tissues | Quantitative measurements | Requires specific primers to distinguish paralogs |
| FISH Mapping | Evolutionary and structural analysis | Visual confirmation of genomic location | Limited resolution at sequence level |
| Retroviral Transduction | In vivo functional studies | Has been successful in chicken models | Species differences may affect translation to humans |
| Epigenetic Profiling | Understanding variable expression | Identifies regulatory mechanisms | Complex interpretation of results |
When studying DGCR6L, researchers should consider approaches that have been successful with DGCR6, such as retrovirus-based gene transduction to deliver sense and antisense constructs to neural crest cells in vivo . This technique has revealed the functional impact of DGCR6 on cardiovascular development and the expression of other DiGeorge critical region genes . Additionally, epigenetic profiling is crucial for understanding the variable expression patterns observed in patients .
How does DGCR6L influence neural crest cell migration and cardiovascular development?
Studies in chicken embryos demonstrate that DGCR6 down-regulates TBX1, impacting neural crest migration within the pharyngeal region . When DGCR6 expression was attenuated using antisense constructs, embryos developed cardiovascular anomalies reminiscent of those found in DiGeorge syndrome . Given the high homology between DGCR6 and DGCR6L, it is reasonable to hypothesize that DGCR6L may also influence neural crest cell migration through similar pathways.
Neural crest cells establish the vasculature of the pharyngeal arch arteries and the thymic capsule, meaning that alterations in their migration affect the morphogenesis of these structures . The experimental evidence suggests that DGCR6 (and potentially DGCR6L) functions in distributing modulator signals from neural crest cells to the heart and pharyngeal arches .
What is the relationship between DGCR6L and other genes in the DiGeorge critical region?
| Gene | Effect of DGCR6 Attenuation | Potential Mechanism | Relevance to DiGeorge Syndrome |
|---|---|---|---|
| TBX1 | Increased expression | Repressor function of DGCR6 | Major contributor to cardiovascular phenotype |
| UFD1L | Increased expression | Repressor function of DGCR6 | Involved in protein degradation pathways |
| HIRA | Decreased expression | Potential activator function | Chromatin remodeling; developmental regulation |
Research in chicken embryo models has demonstrated that DGCR6 functions as a repressor of TBX1 and UFD1L expression, while potentially activating HIRA expression . When DGCR6 expression was attenuated, TBX1 and UFD1L levels increased in hearts and pharyngeal arches, whereas HIRA levels decreased . These expression changes were transient and followed the normal DGCR6 expression profile . This suggests that DGCR6L may similarly influence the expression of other genes in the region, contributing to the complex genetic interactions underlying DiGeorge syndrome.
What evidence links DGCR6L to neuropsychiatric phenotypes in 22q11.2 deletion syndrome?
The 22q11.2 deletion syndrome is associated with an increased risk of schizophrenia and other neuropsychiatric disorders . Studies have provided evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia . When analyzing adult schizophrenic patients with early disease onset or early deviant behaviors, researchers found significant evidence for association with markers in this region .
In particular, transmission of certain haplotypes at the PRODH2/DGCR6 locus was associated with an increased risk of schizophrenia, with an odds ratio of 4.6 (95% CI, 1.4–14.2) in probands with early childhood deviant behaviors . This suggests that DGCR6L, through its position at this locus and potential functional overlap with DGCR6, may contribute to the neuropsychiatric manifestations of 22q11.2 deletion syndrome.
What are the most significant challenges and contradictions in current DGCR6L research?
Researchers face several critical challenges when investigating DGCR6L:
Product Science Overview
DiGeorge Syndrome Critical Region Gene 6-Like (DGCR6L) is a gene located on chromosome 22q11.21. This gene is part of a region implicated in DiGeorge syndrome, a disorder characterized by congenital heart defects, facial dysmorphisms, and immune deficiencies. DGCR6L is one of two functional genes resulting from a duplication event, with its counterpart being DGCR6 .
DGCR6L and DGCR6 share a high degree of similarity, with their proteins being nearly identical. Both genes consist of five exons with conserved intron/exon structures . DGCR6L is expressed in various tissues, including the liver, heart, and skeletal muscle, but is notably absent in adult skeletal muscle and small intestine . The protein encoded by DGCR6L is involved in cell attachment and migration, sharing homology with the Drosophila gonadal protein and the human laminin gamma-1 chain .
The DGCR6L protein is believed to play a role in neural crest cell migration into the third and fourth pharyngeal pouches, which is crucial for the development of several structures in the body . Mutations or deletions in the DGCR6L gene can contribute to the phenotypic manifestations of DiGeorge syndrome and other related disorders, such as velocardiofacial syndrome .
The duplication event that gave rise to DGCR6L and DGCR6 is estimated to have occurred at least 12 million years ago, possibly before the divergence of Catarrhines from Platyrrhines, around 35 million years ago . This suggests that there has been selective evolutionary pressure to maintain the functional integrity of both paralogs.
DGCR6L is associated with several diseases, including prostate cancer and DiGeorge syndrome . The protein’s expression levels are elevated in various human tumor cell lines, indicating its potential role in cancer biology . Understanding the function and regulation of DGCR6L can provide insights into the molecular mechanisms underlying these diseases and aid in the development of targeted therapies.
