TCIRG1基因突变致常染色体隐性遗传性骨硬化症的临床表现及家系分析

The Clinical Phenotypes and Family Study of Autosomal Recessive Osteopetrosis Caused by TCIRG 1 Mutation

目的通过对1例常染色体隐性遗传性骨硬化症(ARO)患儿临床表型和致病基因的研究,提高临床医师对这类少见恶性遗传性疾病的认识。方法对此例ARO患儿进行生化指标检测、腹部超声和骨骼X线检查,同时对本例患儿及其父母、祖父母和外祖父母进行T细胞免疫调节子1基因(TCIRG1)全编码外显子测序,并以100位健康志愿者作为基因突变分析的对照。结果该例患儿血常规示血红蛋白74 g/L,血小板24×109/L;血清碱性磷酸酶(ALP)达1 115 U/L;腹部超声检查示肝脾肿大,上肢和胸部X线可见典型的骨密度增高。患儿及其母亲和外祖母均为TCIRG1基因3号外显子第78位核苷酸发生杂合移码突变(3705C/-)携带者。而在100例健康者中未检出该突变。结论新发现的TCIRG1基因外显子3杂合移码突变(3705C/-)是本例ARO患儿的致病突变位点,此基因突变导致脾肿大、严重贫血和血小板减少等严重的临床表现,因此基因检测对于诊断骨硬化症至关重要。

Objective To study the clinical manifestations and molecular defect in an infant with autosomal recessive osteopetrosis （ARO） to improve the clinicians＇ understanding of this rare and malignant bone disease. Methods The biochemical parameters, abdominal ultrasound and X - ray were examined on this ARO infant. The entire coding region and adjacent splice sites of the T - cell immune regulator 1 （ TCIRG1 ） gene were amplified and sequenced directly in the patient, her parents, her paternal grandparents and her maternal grandparents. One hundred healthy donors were recruited as controls for mutation analysis. Results The infant had severe anemia, thrombopenia and hepatosplenomegaly. Her hemoglobin was only 74 g/L. Her serum ALP level was 1 115 U/L. X - ray images of the chest and upper limb showed typical high bone density. A novel heterozygous frameshift mutation in exon 3 of the TCIRG1 gene （3705C/- ） was detected in the infant, her mother and maternal grand- mother. No controls harbored mutations in the TCIRG1 gene. Conclusion The newly - discovered heterozygous mutation in exon 3 of the TCIRG1 gene was responsible for the Chinese infant with ARO, which clinical manifestations are severe anemia, thrombopenia and splenomegaly. So Genetic Analysis is necessary to diagnose osteopetrosis. The following functional study will investigate the potential mechanism to explain the elevated level of serum ALP and the existence of ARO in patient with monoallelic mutation.