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

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.

Frequency of Congenital Anomalies in the Brazilian Midwest and the Association with Maternal Risk Factors: Case-control Study

“…[8][9][10] The etiology of CNS anomalies is multifactor and involves complex interactions between genetic and environmental factors, constituting one of the most common congenital defects. 9,21,22 Among the anomalies of the CNS observed in this study, hydrocephalus and anencephaly were the most reported changes, which is similar to other studies that also reported hydrocephalus 8,14,17,23 and the anencephaly 8,15,17,24 among the most common malformations.…”

Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children’s Health

“…A recent meta-analysis suggested maternal smoking during pregnancy as a high-risk factor for neural tube defects 36 . TRIM36 is expressed in the developing brain and is thought to be indispensable for somite formation 37 ; lack of TRIM36 due to a homozygous mutation has been reported to result in autosomal recessive anencephaly 38 . Recently, TRIM36 hypermethylation has been linked to a cell-transformation effect of Benzo[a]pyrene, a polycyclic aromatic hydrocarbon found in tobacco smoke, in bronchial epithelial cells 39 .…”

Prevalence and Association of Congenital Anomalies According to the Maternal Body Mass Index: Cross-Sectional Study

“…[21][22][23] The etiology of CNS malformations is multifactorial, involving complex interactions between genetic and environmental factors, constituting one of the most common congenital defects. 22,24,25 Sunitha et al 22 analyzed 360 pregnant women with fetuses presenting structural abnormalities, and also observed a higher frequency of CNS anomalies (37%), followed by genitourinary system abnormalities (20%) and multiple CAs (11%). In addition, other studies have shown the higher prevalence of genitourinary system malformations and of genitourinary system malformations.…”