JAM3 – Porencephaly-Microcephaly-Bilateral Congenital Cataract Syndrome

The autosomal recessive disorder caused by biallelic mutations in JAM3 manifests as porencephaly-microcephaly-bilateral congenital cataract syndrome (Porencephaly-Microcephaly-Bilateral Congenital Cataract Syndrome). Affected neonates present with catastrophic intracranial hemorrhages, subependymal calcifications, congenital cataracts, progressive microcephaly, failure to thrive, and often early mortality despite intensive care.

Initial linkage analysis in a large consanguineous family identified a homozygous splice-donor variant c.612+1G>T leading to frameshift and premature termination (p.Asn192fs) (LOD 6.15) (PMID:21109224). Subsequent sequencing in three additional unrelated families revealed homozygous mutations c.2T>G (p.Met1Arg), c.346G>A (p.Glu116Lys), and c.656G>A (p.Cys219Tyr) (PMID:23255084). Research-based genome sequencing uncovered a deep intronic variant c.256+1260G>C that disrupts splicing, confirmed by RNA studies (PMID:34159711). A recent case report described a novel loss-of-function JAM3 allele in a fetus with prenatal cataracts and brain anomalies (PMID:37780041).

The mutational spectrum comprises at least seven pathogenic alleles: two frameshift duplications (c.572dup, c.745dup), one splice-site (c.612+1G>T), one deep intronic (c.256+1260G>C), one start-loss (c.2T>G), and two missense changes (c.346G>A, c.656G>A). Representative variant: c.2T>G (p.Met1Arg).

Segregation analysis showed co-segregation of the splice-site and missense mutations in all affected members of the original pedigree (LOD 6.15) and consistent homozygosity in three independent families (PMID:21109224; PMID:23255084).

Functional assays demonstrated significant ER retention of the p.Cys219Tyr mutant and loss of partner interaction for p.Glu116Lys (PMID:23255084). RNA analyses confirmed aberrant splicing for c.256+1260G>C and c.612+1G>T, leading to frameshift and nonsense‐mediated decay (PMID:34159711).

Together, multi-family genetic and experimental evidence support a loss-of-function mechanism in JAM3, impairing endothelial integrity in brain vasculature and lens development. Inclusion of JAM3 in diagnostic gene panels for congenital cataracts, hemorrhagic brain injury, and microcephaly is clinically warranted. Key take-home: Biallelic JAM3 mutations cause a distinct autosomal recessive porencephaly-microcephaly-bilateral cataract syndrome via confirmed loss-of-function pathogenesis.

References

• American Journal of Human Genetics • 2010 • A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. PMID:21109224
• Human Mutation • 2013 • Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. PMID:23255084
• American Journal of Medical Genetics Part A • 2021 • Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges. PMID:34159711
• Frontiers in Pediatrics • 2023 • Case report: Novel insights into hemorrhagic destruction of the brain, subependymal calcification, and cataracts disease. PMID:37780041

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