An unusual and novel heterozygous TCIRG1 mutation causes infantile ma-lignant osteopetrosis / 中国病理生理杂志

ABSTRACT

[ ABSTRACT] AIM: To investigate the underlying genetic changes of a Chinese patient with infantile malignant osteopetrosis ( IMO) .IMO is a monogenic disease, mostly caused by mutations of TCIRG1 and CLCN7 genes.The former is believed a homozygous gene and only cause the disease in homozygous or compound heterozygous status.However, it has been reported that heterozygous mutations also cause the disease in 6 non-Chinese cases.METHODS:Genomic DNA was extracted from peripheral blood of the patient and his parents.All exons and splice sites of TCIRG1 and CLCN7 genes were amplified by PCR followed by Sanger sequencing.Mutation detection in the 2 genes was also investigated in the parents. Haplotypes were constructed by variations obtained in mutation detection and microsatillites flanking TCIRG1 gene in the family by Cyrillic.Chromosomal microarray analysis ( CMA) was performed to detect copy number variations ( CNV) of the patient and his mother.RESULTS:A novel mutation c.449_452delAGAG ( p.Gln149Glnfs16) was detected in the pa-tient.This mutation truncated 666 amino acids at the C terminal of the V-ATPase 116 kD isoform a3 protein.It wiped out the entire ATPase V0 complex and was predicted to result in total loss of protein function.This mutation was also detected in the patient’ s father.No pathogenic mutation was detected in CLCN7 gene.CMA did not reveal any CNV involving TCIRG1 or CLCN7 gene.CONCLUSION:We reported a novel heterozygous mutation of TCIRG1 gene causing IMO.This represents the first IMO case in China caused by heterozygous TCIRG1 gene mutation.