Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.

TitleBiallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.
Publication TypeJournal Article
Year of Publication2016
AuthorsJerber, J, Zaki, MS, Al-Aama, JY, Rosti, ROzgur, Ben-Omran, T, Dikoglu, E, Silhavy, JL, Caglar, C, Musaev, D, Albrecht, B, Campbell, KP, Willer, T, Almuriekhi, M, Çağlayan, AOkay, Vajsar, J, Bilguvar, K, Ogur, G, Jamra, RAbou, Günel, M, Gleeson, JG
JournalAm J Hum Genet
Volume99
Issue5
Pagination1181-1189
Date Published2016 Nov 03
ISSN1537-6605
Abstract

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

DOI10.1016/j.ajhg.2016.09.007
Alternate JournalAm. J. Hum. Genet.
PubMed ID27773428
PubMed Central IDPMC5097947
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 GM077243 / GM / NIGMS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54 NS053672 / NS / NINDS NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States