GOSR2 Human

What is GOSR2 and what is its primary function in human cells?

GOSR2 encodes a transmembrane protein belonging to the SNARE (soluble-NSF-attachment-protein-receptor) family of vesicle locking proteins, which mediate membrane fusion during transit of proteins to and from the endoplasmic reticulum (ER). The protein is critical for ER-Golgi transport and Golgi maintenance, functioning as a key component in the vesicular trafficking machinery . GOSR2 specifically localizes to the cis-Golgi and binds the SNARE-Qa molecule syntaxin-5/Sed5p, forming part of the SNARE complex that facilitates membrane fusion . This protein is essential for early development, as homozygous deficiency leads to embryonic lethality in mouse models, highlighting its fundamental importance in cellular physiology .

What are the known human disease associations with GOSR2 mutations?

GOSR2 mutations are associated with several distinct phenotypes depending on the specific genetic variant. The most well-documented condition is progressive myoclonus epilepsy (PME), a severe epilepsy syndrome characterized by an early disease onset (around three years of age) with core neurological symptoms including lack of motor coordination, muscle jerks, and generalized epilepsy . This condition is primarily caused by the p.Gly144Trp mutation, a Northern European founder allele .

Other disease associations include:

• Congenital profound recessive non-syndromic hearing loss (associated with GOSR2 c.1A>C, p.Met1Leu mutation)

• A more severe phenotype combining rapidly progressive epilepsy and muscular dystrophy (caused by compound heterozygosity for GOSR2 p.Gly144Trp and GOSR2 c.2T>G, p.Met1Arg)

• Hypertension in white populations (associated with the GOSR2 Lys67Arg variant)

How is GOSR2 expression regulated at the transcriptional and translational levels?

GOSR2 expression is regulated through several mechanisms:

• Transcriptional regulation: While specific transcriptional regulators are not extensively described in the provided search results, GOSR2 has been shown to have tissue-specific expression patterns.

• Translational regulation: GOSR2 translation can be initiated from non-AUG start codons, as demonstrated in the case of the c.1A>C variant. The efficiency of translation is heavily influenced by the Kozak sequence context (GCCGCCACC|AUGG being the consensus) . When the conventional AUG start codon is altered, the strength of the surrounding Kozak sequence becomes particularly important in determining translation efficiency. This was evident in family CJ where the relatively mild effect of GOSR2 c.1A>C, p.Met1Leu mutation depended not only on the specific mutation in codon 1 but also on the close-to-ideal Kozak sequence at positions -1 to -4 .

• Post-translational regulation: GOSR2 function is likely regulated through interactions with various SNARE complex binding partners in different tissues.

What experimental models are used to study GOSR2 function and pathogenic mechanisms?

Researchers employ several experimental models to investigate GOSR2 function and disease mechanisms:

Drosophila (Fruit Fly) Model:
The Drosophila model has proven particularly valuable for studying GOSR2-related pathologies. The close relationship between human and Drosophila genes allows researchers to mutate the fly ortholog of GOSR2 and study the consequences . This model has revealed neuronal abnormalities underlying GOSR2-related disorders that ultimately give rise to coordination defects and epilepsy. The short generation time and inexpensive maintenance make Drosophila an efficient model system .

Cell Culture Systems:
Knockdown studies of GOSR2 in cell culture have demonstrated loss of ER-Golgi transport and interference with Golgi maintenance, providing insights into the cellular consequences of GOSR2 dysfunction .

Human Patient Samples:
Collection of DNA samples from patients with progressive myoclonus epilepsy has enabled researchers to identify and characterize new GOSR2 mutations. This approach led to the discovery of a previously unknown mutation in GOSR2 .

Mouse Models:
The International Mouse Phenotyping Consortium has demonstrated that homozygous deficiency of Gosr2 is embryonic lethal, highlighting its essential function in development .

How do different GOSR2 mutations contribute to distinct disease phenotypes?

The relationship between GOSR2 mutations and phenotypes demonstrates remarkable specificity, with different mutations causing distinct clinical presentations:

The tissue-specific effects of different mutations likely relate to the variable composition of SNARE complexes across tissues. For example, the synaptic SNARE complex of brain neuronal cells differs from the analogous SNARE complex of inner ear hair cells in both structural components and protein regulators . This explains why mutations affecting specific binding interfaces may impact some tissues while sparing others.

What molecular mechanisms explain the GOSR2 mutation paradox in hearing versus neurological phenotypes?

The paradox of GOSR2 mutations causing either severe neurological disease with normal hearing (p.Gly144Trp) or isolated hearing loss (c.1A>C) likely reflects the complex biology of tissue-specific SNARE complexes:

This paradox parallels observations with other SNARE-related proteins: mutations in the inner-ear-specific synaptic SNARE-associated protein otoferlin (OTOF) cause hearing loss without neurological features, while mutations in brain-neuronal-specific SNARE complex components (STX1B, VAMP2, SNAP25, STXBP1, UNC13A) cause epilepsy without hearing loss .

What genomic and proteomic techniques are most effective for studying GOSR2 function?

Several complementary techniques have proven valuable for GOSR2 research:

Whole Genome Sequencing (WGS):
WGS has been instrumental in identifying novel GOSR2 mutations. In family CJ, WGS of 12 family members revealed linkage of hearing loss to a 4.8MB region on chromosome 17q21.3, harboring the GOSR2 c.1A>C variant .

Targeted Genetic Screening:
Screening of specific genes in patient cohorts has enabled the discovery of new GOSR2 mutations. This approach led to the identification of a previously unknown mutation in patients with progressive myoclonus epilepsy .

Translation Efficiency Assays:
Analysis of translation from non-AUG start codons and the impact of Kozak sequence variations has provided insights into how mutations affecting translation initiation influence GOSR2 expression levels .

Cellular Localization Studies:
Determining the subcellular localization of wild-type and mutant GOSR2 proteins helps understand how mutations impact protein trafficking and Golgi maintenance .

Protein-Protein Interaction Analysis:
Investigating interactions between GOSR2 and other SNARE complex components in different tissues reveals how mutations may disrupt specific binding interfaces .

How can researchers effectively model GOSR2 dysfunction in vitro and in vivo?

Researchers can employ multiple complementary approaches to model GOSR2 dysfunction:

CRISPR/Cas9 Gene Editing:
Generation of specific GOSR2 mutations in cellular or animal models using CRISPR/Cas9 technology allows precise recapitulation of human disease mutations.

Drosophila Models:
The fruit fly provides a powerful and efficient system for modeling GOSR2 mutations. The relationship between Drosophila and human genes is close enough that human GOSR2 mutations can be modeled in the fly ortholog, revealing neuronal defects that underlie coordination problems and epilepsy .

Patient-Derived Cells:
Lymphoblastoid cell lines (LCLs) or induced pluripotent stem cells (iPSCs) from patients with GOSR2 mutations provide valuable tools for investigating cellular phenotypes in the context of the patients' genetic background .

Tissue-Specific Conditional Knockout Models:
Since complete GOSR2 knockout is embryonic lethal, tissue-specific conditional knockout models can help elucidate the function of GOSR2 in specific cell types and organs.

Translation Reporter Assays:
To study the impact of mutations affecting translation initiation, reporter constructs containing wild-type or mutant Kozak sequences and start codons can be used to quantify translation efficiency .

What is the relationship between GOSR2 variants and cardiovascular disease risk?

GOSR2 variants, particularly the Lys67Arg polymorphism (rs197922), have been associated with hypertension and blood pressure regulation in specific populations:

In the Atherosclerosis Risk in Communities (ARIC) study involving 3,528 blacks and 9,861 whites, the GOSR2 Lys67 allele was significantly associated with:

• Hypertension in whites (odds ratio (OR) = 1.09, P = 0.01) but not blacks (OR = 0.96, P = 0.47)

• Increased systolic blood pressure (SBP) in both whites (0.87 mm Hg, P < 0.001) and blacks (1.05 mm Hg, P = 0.05)

This association was also observed in the Women's Genome Health Study (WGHS), where the GOSR2 SNP was associated with SBP (OR = 1.03, P = 0.04) . The association remained unchanged after adjustment for antihypertensive medication use (OR = 1.03), though it was no longer statistically significant (P = 0.11) .

The biological mechanism underlying this association remains to be fully elucidated but may involve GOSR2's role in trafficking proteins involved in blood pressure regulation.

How should researchers approach genetic counseling for families with GOSR2-related disorders?

Genetic counseling for families with GOSR2-related disorders should consider several key aspects:

Inheritance Pattern Assessment:
GOSR2-related disorders typically follow an autosomal recessive inheritance pattern, as seen in family CJ where parents were first cousins with normal hearing and affected children had biallelic mutations . Accurate determination of inheritance patterns is essential for recurrence risk assessment.

Phenotype Prediction:
Counseling should incorporate the genotype-phenotype correlations observed in GOSR2-related disorders. Different mutations lead to distinct clinical presentations:

• p.Gly144Trp: Progressive myoclonus epilepsy with ataxia

• c.1A>C, p.Met1Leu: Non-syndromic hearing loss

• Compound heterozygosity: More severe combined phenotypes

Comprehensive Kozak Sequence Evaluation:
For variants affecting translation initiation, evaluation should include the entire Kozak sequence (at least positions -4 to +4), as the efficiency of translation from non-AUG start codons depends on the surrounding sequence context .

Population-Specific Considerations:
The frequency of specific GOSR2 variants varies across populations. For example, the p.Gly144Trp mutation appears to be a Northern European founder allele, while the c.1A>C variant was identified in a Palestinian family .

What are the most promising approaches for developing therapeutic interventions for GOSR2-related disorders?

Several therapeutic approaches hold potential for GOSR2-related disorders:

Enhanced Translation Strategies:
For mutations affecting translation efficiency like c.1A>C, interventions that enhance translation from non-AUG start codons could potentially increase GOSR2 protein levels to therapeutically beneficial thresholds .

SNARE Complex Modulation:
Targeting specific components of the SNARE complex to compensate for altered GOSR2 function represents another potential approach, particularly in cases where the mutation affects specific binding interactions rather than causing complete loss of function .

Tissue-Targeted Approaches:
Given the tissue-specific effects of different GOSR2 mutations, therapies could be designed to target the affected tissues (e.g., inner ear for hearing loss variants, neurons for epilepsy variants) .

Gene Therapy:
Introduction of functional GOSR2 copies through viral vectors or other gene delivery methods could address recessive loss-of-function mutations.

Animal Model Drug Screening:
The Drosophila model of GOSR2 dysfunction provides an efficient platform for screening potential therapeutic compounds that might mitigate neuronal defects associated with GOSR2 mutations .

How might advances in understanding GOSR2 function contribute to broader knowledge of vesicular trafficking disorders?

Research into GOSR2 has broader implications for understanding vesicular trafficking disorders:

• Tissue-Specific SNARE Complex Biology: The paradoxical phenotypes associated with different GOSR2 mutations highlight the importance of tissue-specific binding partners and SNARE complex composition, a principle that likely extends to other vesicular trafficking disorders .

• Translation Initiation Mechanisms: The discovery of functional translation from non-AUG start codons in GOSR2 provides insights into alternative translation initiation mechanisms that may be relevant for other genes and disorders .

• Integration with Other Trafficking Pathways: Understanding how GOSR2 dysfunction affects specific cellular pathways can illuminate the integration of ER-Golgi trafficking with other cellular processes, potentially revealing unexpected disease mechanisms in other contexts.

• Therapeutic Target Identification: Characterization of the molecular pathways affected by GOSR2 mutations may identify novel therapeutic targets for other vesicular trafficking disorders with shared pathological mechanisms.

• Model System Development: The successful use of Drosophila to model GOSR2-related neuronal defects establishes a paradigm for studying other trafficking disorders in this efficient model system .