{"doi":"10.1093/hmg/ddad066","title":"A paradoxical genotype-phenotype relationship: Low level of <i>GOSR2</i> translation from a non-AUG start codon in a family with profound hearing loss","abstract":"Translation initiation in eukaryotic cells typically begins at an AUG start codon in a Kozak sequence (1). The consensus translation initiation sequence is GCCGCCACC|AUGG, with variations leading to differences in translation efficiency (2,3). Variable efficiency of Kozak sequences and their embedded start codons may explain congenital profound recessive non-syndromic hearing loss due to Golgi snap receptor complex member 2 (GOSR2) in an extended consanguineous Palestinian family (Fig. 1A). This result was unexpected, given that known pathogenic alleles of GOSR2 are responsible for a severe recessive neurological phenotype, but with normal hearing. The paradox may be resolved by the combination of unique features of the first codon mutation in the family, and differences in GOSR2 binding partners of soluble-NSF-attachment-protein-receptor (SNARE) complexes in brain neurons versus GOSR2 binding partners of SNARE complexes in the inner ear. In family CJ, four children in two sibships have congenital profound hearing loss. The parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. As young adults, none of the deaf individuals had any signs of epilepsy, ataxia, other severe neurological abnormalities or other syndromic features (see also Supplementary Material, Supplemental Methods). Whole genome sequencing of 12 members of family CJ yielded linkage of hearing loss, under an autosomal recessive model, to a region of 4.8 MB on chromosome 17q21.3. The region harbored only one likely candidate allele, GOSR2 c.1A > C, p.Met1Leu (NM_054022) (Supplementary Material, Table S1). This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry. The likelihood is <0.005 that this variant co-segregates by chance with hearing loss in the family. GOSR2 is ubiquitously expressed, including in the inner ear (4). GOSR2 encodes a transmembrane protein in the SNARE family of vesicle locking proteins, which mediate membrane fusion during transit of proteins to and from the endoplasmic reticulum (ER) (5). The International Mouse Phenotyping Consortium has shown that homozygous deficiency of Gosr2 is embryonic lethal (mousephenotype.org). Knockdown of GOSR2 leads to a loss in ER-Golgi transport and interferes with Golgi maintenance (6). In humans, homozygosity for a Northern European founder allele, GOSR2 p.Gly144Trp, causes a severe form of childhood-onset progressive myoclonic epilepsy with ataxia, but with apparently normal hearing (7,8), Compound heterozygosity for GOSR2 p.Gly144Trp and GOSR2 c.2T>G, p.Met1Arg, leads to the most severe GOSR2-related phenotype, including both rapidly progressive epilepsy and muscular dystrophy (8,9). Previous analysis of start codons and Kozak sequences genome-wide (3) predicted that mutation of codon 1 from ATG to AGG (Met1Arg, the severe European allele) would nearly abolish translation, but that mutation of codon 1 from ATG to CTG (Met1Leu, the allele of family CJ) would retain partial translation (Fig. 1B). We tested this prediction by measuring GOSR2 protein in Epstein-Barr virus (EBV)-transformed human lymphoblast cell line (LCL) lysates from individuals in family CJ (Fig. 1C). Western blot revealed that GOSR2 protein was detectable in homozygous affected children III-6 and III-7, but significantly reduced, to 8.5% and 3.4% respectively, of protein levels in controls; protein of heterozygous unaffected carrier II-4 was modestly reduced compared with control. Gels were run sufficiently long to rule out translation from the downstream start codon, methionine-19, which would result in a protein of size ~23 kD. Clinical and cellular features of GOSR2 p.Met1Leu. (A) Family CJ with congenital non-syndromic sensorineural hearing loss in four children (filled symbols), with genotypes at GOSR2 c.1A>C, p.Me","journal":"Human Molecular Genetics","year":2023,"id":386116,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491905,"name":"Ryan J. Carlson","orcid":"0000-0001-8311-481X","position":1,"is_corresponding":false},{"id":557981,"name":"Grace Rabie","orcid":"0000-0003-0613-7086","position":2,"is_corresponding":false},{"id":6976,"name":"Ming K. Lee","orcid":"0000-0002-4529-9259","position":3,"is_corresponding":false},{"id":268356,"name":"Süleyman Gülsüner","orcid":"0000-0002-3897-1238","position":4,"is_corresponding":false},{"id":6947,"name":"Tom Walsh","orcid":"0000-0002-8875-0310","position":5,"is_corresponding":false},{"id":377172,"name":"Karen B. Avraham","orcid":"0000-0002-4913-251X","position":6,"is_corresponding":false},{"id":297307,"name":"Moien Kanaan","orcid":"0000-0002-3227-4685","position":7,"is_corresponding":false},{"id":6987,"name":"Mary‐Claire King","orcid":"0000-0001-9426-1743","position":8,"is_corresponding":false},{"id":491904,"name":"Amal Abu Rayyan","orcid":"0000-0002-8061-5173","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:17:56.803401Z","pmid":"37074134","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}