SNX3 – MMEP syndrome

SNX3 (HGNC:11174) was initially implicated in MMEP syndrome (MONDO:0011045) through a t(6;13)(q21;q12) translocation disrupting SNX3 in a single patient. A targeted sequencing study of SNX3 coding regions, splice sites, untranslated regions, and conserved promoter elements in five unrelated MMEP or related‐phenotype probands—including the original translocation case—identified no synonymous or nonsynonymous SNX3 variants (5 probands screened (PMID:17655765)). A solitary noncoding regulatory variant, previously reported in microcephaly, was found in one patient but was absent in 250 controls (PMID:17655765). No segregation data or recurrent SNX3 alleles were observed across families, arguing against a Mendelian inheritance via coding mutations. The negative case series thus fails to support a dominant or recessive SNX3 coding‐variant mechanism in MMEP.

Functional characterization of the SNX3 ortholog Grd19p in Saccharomyces cerevisiae reveals its role in the selective retrograde retrieval of late‐Golgi membrane proteins from the prevacuolar compartment (PMID:9456318). Grd19p null mutants mislocalize TGN cargo such as A‐ALP and Kex2p to the vacuole but show minimal impact on bulk vacuolar protein sorting, confirming a specific vesicle‐sorting function. However, no patient‐derived or vertebrate model systems have linked SNX3 dysfunction to neurodevelopmental malformations or the MMEP phenotype. The absence of disease‐relevant functional assays and the lack of coding mutations in patients dispute a causal role for SNX3 in MMEP syndrome. Key Take-home: SNX3 is unlikely to be a primary contributor to MMEP syndrome via coding variants and should be deprioritized in diagnostic testing for this condition.

References

• BMC Medical Genetics • 2007 • Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes. PMID:17655765
• The Journal of cell biology • 1998 • Retrieval of resident late-Golgi membrane proteins from the prevacuolar compartment of Saccharomyces cerevisiae is dependent on the function of Grd19p. PMID:9456318

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