SMPX – X-linked Hearing Loss 4

SMPX has been implicated in X-linked nonsyndromic sensorineural hearing loss (DFNX4, X-linked Hearing Loss 4). Pathogenic variants, notably truncating and splice-site changes, lead to progressive auditory impairment predominantly in male hemizygotes (PMID:21893181).

In a large Dutch DFNX4 pedigree, linkage analysis and sequencing identified a truncating variant p.Glu72Ter in SMPX segregating with hearing loss in 25 carriers, including 10 hemizygous males and 14 heterozygous females, with one 25-year-old female exception (PMID:21893181). A Han Chinese family harbored a donor splice-site variant c.132+1G>A (p.Met45GlyfsTer16) in the proband, with two obligate female carriers, indicating X-linked recessive inheritance (PMID:31478598).

Affected males exhibited early onset between 2–10 years (mean 3.3 years), rapid progression in the first two decades, and high-frequency deterioration, while female carriers showed later onset (3–48 years, mean 26.4 years), milder thresholds, and greater interaural variability (PMID:21893181). Longitudinal regression confirmed significant progression in multiple individuals of both sexes.

Functional assays of the c.132+1G>A variant demonstrated aberrant splicing with four alternative transcripts, resulting in a frameshift and premature termination codon that triggered nonsense-mediated mRNA decay, consistent with a loss-of-function mechanism (PMID:31478598).

No conflicting evidence has been described; in silico analyses predict additional SMPX missense variants as deleterious, supporting structural impact on protein stability.

Together, segregation in two unrelated pedigrees, concordant audiometric profiles, and functional validation solidify a strong gene-disease relationship. SMPX screening is recommended for males with familial sensorineural hearing loss and for female carriers in at-risk lineages.

References

• Hearing Research • 2011 • Variable degrees of hearing impairment in a Dutch DFNX4 (DFN6) family. PMID:21893181
• Molecular Genetics & Genomic Medicine • 2019 • Whole-exome sequencing identifies a donor splice-site variant in SMPX that causes rare X-linked congenital deafness. PMID:31478598

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