Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria.
Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development.
O'Driscoll
Mary C
MC
University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, UK.
Daly
Sarah B
SB
Urquhart
Jill E
JE
Black
Graeme C M
GC
Pilz
Daniela T
DT
Brockmann
Knut
K
McEntagart
Meriel
M
Abdel-Salam
Ghada
G
Zaki
Maha
M
Wolf
Nicole I
NI
Ladda
Roger L
RL
Sell
Susan
S
D'Arrigo
Stefano
S
Squier
Waney
W
Dobyns
William B
WB
Livingston
John H
JH
Crow
Yanick J
YJ
D000818:Animals; D001483:Base Sequence; D002114:Calcinosis / Q000134:cerebrospinal fluid / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D054220:Malformations of Cortical Development / Q000134:cerebrospinal fluid / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D062793:Occludin; D012984:Software; D019108:Tight Junctions / Q000235:genetics*
D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse