SPATA7 and Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is an autosomal recessive, early-onset retinal dystrophy characterized by severe visual impairment from birth. SPATA7 encodes a ciliary protein expressed in photoreceptor connecting cilia and was mapped to the LCA3 locus on chromosome 14 (PMID:20104588). Loss-of-function SPATA7 variants lead to rod–cone dystrophy consistent with LCA type II.

Initial mutation screening in a cohort of 134 unrelated LCA patients identified SPATA7 pathogenic variants in 4 families (4/134) (PMID:20104588). Six distinct SPATA7 mutations were reported, including both start-loss (c.3G>T (p.Met1Ile)) and splice-site changes. In a South Indian series of 11 consanguineous LCA families, SPATA7 mutations were found in 1 family, segregating as homozygous alleles and absent in 200 controls (PMID:26147992).

Targeted screening of 141 LCA and early-onset retinal dystrophy (EORD) cases uncovered SPATA7 variants in 5 unrelated families, accounting for 1.7% of disease in that cohort (PMID:21310915). The variant spectrum includes frameshift (e.g., c.265_268del (p.Leu89fs)), nonsense (e.g., c.253C>T (p.Arg85Ter)), and splice-site changes, all predicted to abrogate protein function.

A comprehensive assessment of 5,090 probands identified SPATA7 mutations in 12 Chinese patients across 10 families. Combined with literature data (n=60 families), 120 mutant alleles were collated: 93.3% truncating, 5.0% missense, and 1.7% small in-frame indels (PMID:31908400). Typical SPATA7-associated fundus changes include narrow arterioles, preserved macula, and diffuse midperipheral RPE atrophy.

Functional studies demonstrate high SPATA7 expression in retina, brain, and testis, and SPATA7 knockout mice exhibit photoreceptor degeneration and disrupted ciliary protein complexes, confirming a loss-of-function mechanism (PMID:32799588). Animal models recapitulate key human phenotypes and support SPATA7’s role in photoreceptor survival.

Collectively, biallelic SPATA7 variants cause autosomal recessive LCA with a predominance of truncating alleles, consistent segregation across multiple families, and concordant functional data from knockout models. SPATA7 screening is recommended in LCA diagnostic panels, and variant interpretation should prioritize protein-truncating changes. Key take-home: SPATA7 loss-of-function mutations are a validated cause of autosomal recessive LCA, guiding molecular diagnosis and genetic counseling.

References

• Human mutation • 2010 • Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. PMID:20104588
• PLoS one • 2015 • Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families. PMID:26147992
• Investigative ophthalmology & visual science • 2011 • Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. PMID:21310915
• PLoS one • 2011 • Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PMID:21602930
• Molecular vision • 2019 • Spectrum, frequency, and genotype-phenotype of mutations in SPATA7. PMID:31908400
• Ophthalmic genetics • 2020 • The spermatogenesis-associated protein-7 (SPATA7) gene - an overview. PMID:32799588

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