A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family

Singh, Nivedita and Bhat, Vishwanath Kumble and Tiwari, Ankana and Kodaganur, Srinivas G and Tontanahal, Sagar J and Sarda, Astha and Malini, K V and Kumar, Arun (2017) A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. In: HUMAN MOLECULAR GENETICS, 26 (6). pp. 1104-1114.

PDF Hum_Mol_Gen_26-6_1104_2017.pdf - Published Version Restricted to Registered users only Download (1MB) | Request a copy

Abstract

Anencephaly (APH) is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to APH. APH shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of APH has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c. 1522C > A (p. Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive APH in an Indian family. The TRIM36 gene is expressed in the developing brain, suggesting a role in neurogenesis. In silico analysis showed that proline at codon position 508 is highly conserved in 26 vertebrate species, and the mutation is predicted to affect the conformation of the B30.2/SPRY domain of TRIM36. Both in vitro and in vivo results showed that the mutation renders the TRIM36 protein less stable. TRIM36 is known to associate with microtubules. Transient expression of the mutant TRIM36 in HeLa and LN229 cells resulted in microtubule disruption, disorganized spindles, loosely arranged chromosomes, multiple spindles, abnormal cytokinesis, reduced cell proliferation and increased apoptosis as compared with cells transfected with its wild-type counterpart. The siRNA knock down of TRIM36 in HeLa and LN229 cells also led to reduced cell proliferation and increased apoptosis. We suggest that microtubule disruption and disorganized spindles mediated by mutant TRIM36 affect neural cell proliferation during neural tube formation, leading to APH.

Item Type:	Journal Article
Publication:	HUMAN MOLECULAR GENETICS
Additional Information:	Copy right for this article belongs to the OXFORD UNIV PRESS, GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	10 Jun 2017 04:40
Last Modified:	10 Jun 2017 04:40
URI:	http://eprints.iisc.ac.in/id/eprint/57179

Actions (login required)

View Item