TMTC3 – Periventricular Nodular Heterotopia

TMTC3 encodes a transmembrane O-mannosyltransferase targeting cadherins and is associated with an autosomal recessive form of periventricular nodular heterotopia (PVNH) characterized by neuronal migration defects, seizures, and intellectual disability. Affected individuals typically present in infancy with intractable epilepsy, global developmental delay, and hypotonia.

In a multi-sibling study, compound heterozygous variants in TMTC3 (c.212G>A (p.Arg71His) and c.1554del (p.Lys518fsTer?)) were identified in four affected siblings; three siblings exhibited brain imaging–confirmed PVNH segregating with disease status across the kindred (4 probands, 3 segregations) (PMID:28973161).

A separate case report described a 22-month-old boy with white matter plaques, small frontal lobes, myelin dysplasia, microcephaly, infantile spasms, and bilateral single transverse palmar creases carrying novel compound variants c.1123G>A (p.Glu375Lys) and c.1126_1129del (p.Arg376TyrfsTer13), expanding the phenotypic spectrum toward a cobblestone-like presentation overlapping with PVNH features (PMID:32973946).

Functional analyses in patient-derived cells demonstrated markedly reduced TMTC3 transcript levels and absence of protein compared to controls, supporting a loss-of-function mechanism (PMID:28973161).

Neuron-specific knockdown of the Drosophila TMTC3 ortholog resulted in increased seizure susceptibility that was rescued by human TMTC3 expression, confirming in vivo relevance to epileptogenesis. Biochemical studies further showed that TMTC3 mediates O-mannosylation of E-cadherin, with Xenopus embryonic knockdown causing gastrulation delays rescued by human TMTC3, linking glycosylation defects to cellular adhesion and neuronal migration (PMID:31851597).

Collectively, the genetic segregation in multiple affected siblings, consistent functional deficits in patient cells, in vivo model rescue experiments, and biochemical evidence for disrupted cadherin glycosylation support a Strong ClinGen gene–disease association. TMTC3 sequencing should be considered in patients with PVNH, seizures, and developmental delay to inform diagnosis and genetic counseling.

References

• Human molecular genetics • 2017 • Identification of a novel synaptic protein, TMTC3, involved in periventricular nodular heterotopia with intellectual disability and epilepsy. PMID:28973161
• Experimental and therapeutic medicine • 2020 • Novel compound variants of the TMTC3 gene cause cobblestone lissencephaly-like syndrome: A case report. PMID:32973946
• Molecular biology of the cell • 2020 • Endoplasmic reticulum transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, cellular adherence, and embryonic gastrulation. PMID:31851597

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