Clinical study and genetic analysis of Cornelia de Lange syndrome caused by a novel MAU2 gene variant in a Chinese boy

Abstract

Background: Cornelia de Lange syndrome (CdLS) is mainly characterized by specific facial features, growth retardation, and bone deformities. Seven genes reportedly cause CdLS. Recent research has reported that loss-of-function variants affecting MAU2, which encodes a regulator of the cohesin complex, can cause CdLS. Thus far, only one MAU2-CdLS case has been reported worldwide.

Methods: We detected a novel variant in MAU2 gene, NM_015329, c.526C>T (p.Arg176Trp) in a Chinese patient with CdLS, constructed a plasmid for in vitro transcriptional and protein level analysis, and analyzed the interaction between the MAU2/NIPBL complex using molecular dynamics (MD).

Results: The results showed that the level of the exogenous MAU2 mutant protein was significantly reduced compared with that of the exogenous wild-type protein. However, MD analysis predicted an increased binding free energy between the MAU2 and NIPBL proteins that may impact the structural stability of the complex.

Conclusion: We investigated a MAU2-CdLS case in a Chinese family, which strengthens the association between MAU2 variants and CdLS phenotypes. We therefore propose that MAU2 be included in the CdLS gene screening list.

Keywords: CdLS; Cornelia de Lange syndrome; MAU2; cohesin; genetic testing.

FIGURE 1

Clinical information of the patient with CdLS. (a) The child has facial features including a hairy forehead and face, thick eyebrows with curved arches, long philtrum, thin upper lip, and high jaw arch; (b) The fingers are short, and the fifth finger is bent; (c) Excretory cystourethrography showed right ureteral reflux, and less contrast medium remained in the bladder; (d–f) Abdominal magnetic resonance imaging showed a right duplicate kidney, two sets of renal pelvises converged at the renal hilum, and a slightly dilated proximal ureter. The left kidney was small with a thin wall. CdLS, Cornelia de Lange syndrome.

FIGURE 2

Mutation information of the patient. (a) The results of trio‐WES revealed a heterozygous missense mutation, NM_015329, c.526C>T (p.Arg176Trp), in the MAU2 gene of the patient. His parents and two younger brothers were wild‐type. Sanger sequencing confirmed the existence of the mutation; (b) qPCR results showed that the mRNA expression in the MAU2‐WT and MAU2‐MUT groups was significantly higher than that in the NC‐plasmids group, but there was no significant difference between the MAU2‐WT and MAU2‐MUT groups, indicating that the mutation may not affect the transcription process of MAU2; (c) Western blot analysis showed that the MAU2 protein expression of the MAU2‐MUT group (p.Arg176Trp) was significantly lower (22%) than that of the MAU2‐WT group. *p < 0.05; **p < 0.01; ***p < 0.001.

FIGURE 3

Structural prediction and analysis of the mutant protein. (a) The root mean square evolution was used to monitor the balance of wild‐type and mutant MAU2/NIPBL complexes, and the wild‐type complex structure diagram was formed; (b) A hydrogen bond was formed between the wild‐type MAU2 Arg176 and Glu173, and between the surrounding residues Arg184 and Glu181. In the wild‐type NIPBL/MAU2 complex, a hydrogen bond was formed between NIPBL Cys2392 and MAU2 Glu173, and between NIPBL Thr1943 and MAU2 Arg176. However, mutant MAU2 p.Arg176Trp broke the hydrogen bond with Glu173, while Arg184 formed a hydrogen bond with Glu173. In the mutant NIPBL/MAU2 complex, NIPBL Cys2392 formed a hydrogen bond with mutant MAU2 Glu173, and mutant MAU2 Trp176 formed a hydrophobic interaction with NIPBL, which may weaken the stability of the mutant NIPBL/MAU2 complex. CdLS, Cornelia de Lange syndrome; MAU2‐MUT, MAU2‐mutation plasmids; MAU2‐WT, MAU2‐wild type plasmids; NC‐plasmids, no carrier control plasmids; qPCR, quantitative polymerase chain reaction.