Recessive LAMC3 mutations cause malformations of occipital cortical development.
Recessive LAMC3 mutations cause malformations of occipital cortical development.
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大脑皮层形态的区域性和种间差异的生物学基础尚不清楚。我们重点研究了有单一受累成员的土耳其血缘家庭，这些家庭有复杂的双侧枕叶皮质旋转异常。通过全外显子组测序，我们初步鉴定了层粘连蛋白γ3基因LAMC3中存在2个碱基的纯合缺失，导致了一个即时提前终止密码子。在另外两个表型几乎相同的受累个体中，我们发现了一个纯合子无义突变和一个复合杂合突变。在人而不是小鼠胎脑中，LAMC3在有丝分裂后皮质板状神经元中丰富，主要定位于躯体树突间。LAMC3的表达在妊娠晚期和婴儿后期达到高峰，与树突发生和突触形成中重要的分子的表达平行。这种不寻常的枕骨畸形的分子基础的发现进一步加深了我们对皮质旋转形成的复杂生物学的理解。
The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.
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