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Discovery of a gene in which mutations lead to an isolated defect of brain development

Sagittal sections of brains. Above a normal individual (corpus callosum in red) and below a patient included in the study (mutated in DCC) where we can see the complete absence of the corpus callosum.

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Marsh AP(1)(2), Heron D(3)(4)(5), Edwards TJ(6)(7), Quartier A(8), Galea C(9), Nava C(3)(10), Rastetter A(10), Moutard ML(11)(12)(13), Anderson V(14), Bitoun P(15), Bunt J(6), Faudet A(3), Garel C(16), Gillies G(1), Gobius I(6), Guegan J(17), Heide S(3)(4), Keren B(3)(10), Lesne F(3), Lukic V(18), Mandelstam SA(2)(19)(20), McGillivray G(21), McIlroy A(14), Meneret A(10)(22), Mignot C(3)(4)(5), Morcom LR(6), Odent S(23)(24), Paolino A(6), Pope K(1), Riant F(25), Robinson GA(26), Spencer-Smith M(14)(27), Srour M(28)(29), Stephenson SE(1)(2), Tankard R(30)(31), Trouillard O(10), Welniarz Q(10)(32), Wood A(14)(33), Brice A(3)(10), Rouleau G(29)(34), Attie-Bitach T(35)(36), Delatycki MB(1)(2)(37), Mandel JL(8)(38), Amor DJ(1)(2), Roze E(10)(22), Piton A(8)(38), Bahlo M(30)(31), Billette de Villemeur T(5)(11)(12)(39), Sherr EH(40), Leventer RJ(2)(41)(42), Richards LJ(6)(43), Lockhart PJ(1)(2), Depienne C(3)(8)(10)(38).

Nat Genet Apr 2017


Feb. 27, 2017

Christel Depienne of Jean-Louis Mandel’s team (currently in Binnaz Yalcin’s team), in collaboration with the clinical research group of Delphine Héron (Hôpital Pitié-Salpêtrière) and neuropediatricians of the Trousseau Hospital (Pr Thierry Billette de Villemeur and Dr Marie-Laure Moutard) and the Australian teams of Paul Lockhart (Melbourne) and Linda Richards (Brisbane), have identified mutations in the first gene responsible for isolated agenesis of the corpus callosum (lack of development of the main brain structure responsible for the communication between the two hemispheres of the brain). Their results are published on February 27th in Nature Genetics.

The two cerebral hemispheres mainly communicate through the corpus callosum, a kind of bridge that allows the passage of the information and participates in particular in the processes of memory and learning. It happens that some people are born without corpus callosum, a condition known as agenesis of the corpus callosum. This cerebral developmental disorder may be associated with intellectual disability of variable severity, or may manifest itself by almost no symptoms, although the absence of the corpus callosum has an impact on cognition, language or humor by example. The detection of this malformation is most often performed during the prenatal period, ie it is visible on ultrasound during the second trimester of pregnancy. The detection of such an in utero malformation then constitutes a real challenge to predict the cognitive outcome of the child to be born. In other cases of adult patients who did not benefit from a pregnancy follow-up, the agenesis of the corpus callosum can be detected incidentally, during an MRI examination carried out for another cause, migraine for example.

 

Christel Depienne and colleagues have studied a specific form of agenesis of the corpus callosum, called isolated since people with this form do not have intellectual disability. Their study, carried out in 9 different families including 4 with people affected over several generations, revealed for the first time dominantly inherited mutations on a specific gene, DCC. The protein encoded by this gene is a netrin 1 receptor and plays a key role in axonal guidance during cerebral development and thus allows the axons, extensions of neurons, to pass from one side of the brain to the other and thus ensuring the connection between the two hemispheres.

The DCC gene had been previously associated with another pathology in humans, congenital mirror movements, which affects the ability of patients to perform different movements of both hands. Patients make involuntary movements on one side of the body, reproducing intentional movements made on the other side of the body. The orientation towards one or the other of these pathologies could have different explanations. On the one hand, the genetic background of the individual, ie the set of specific variants of this individual, and on the other hand sex. Girls appear to be at greater risk of developing agenesis of the corpus callosum and boys more at risk of developing mirror movements, although this rule is not absolute.

 

This discovery helps to better understand the causes of agenesis of the corpus callosum and the normal and pathological development of the brain. Agenesis of the corpus callosum is an important cause of late medical termination of pregnancy. The discovery of the DCC gene could therefore have a major impact in the context of prenatal diagnosis, in particular by allowing to better predict whether or not the unborn child will suffer from intellectual disability.

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