Boyadjiev SA, Kim S‐D, Hata A, Haldeman‐Englert C, Zackai EH, Naydenov C, Hamamoto S, Schekman RW, Kim J. Cranio‐lenticulo‐sutural dysplasia associated with defects in collagen secretion.

Cranio‐lenticulo‐sutural dysplasia (CLSD) is a rare autosomal recessive syndrome manifesting with large and late‐closing fontanels and calvarial hypomineralization, Y‐shaped cataracts, skeletal defects, and hypertelorism and other facial dysmorphisms. The CLSD locus was mapped to chromosome 14q13‐q21 and a homozygous SEC23A F382L missense mutation was identified in the original family. Skin fibroblasts from these patients exhibit features of a secretion defect with marked distension of the endoplasmic reticulum (ER), consistent with SEC23A function in protein export from the ER. We report an unrelated family where a male proband presented with clinical features of CLSD. A heterozygous missense M702V mutation in a highly conserved residue of SEC23A was inherited from the clinically unaffected father, but no maternal SEC23A mutation was identified. Cultured skin fibroblasts from this new patient showed a severe secretion defect of collagen and enlarged ER, confirming aberrant protein export from the ER. Milder collagen secretion defects and ER distention were present in paternal fibroblasts, indicating that an additional mutation(s) is present in the proband. Our data suggest that defective ER export is the cause of CLSD and genetic element(s) besides SEC23A may influence its presentation.