背景:由于破骨细胞骨吸收受损,常染色体显性骨症(ADO)是一种罕见的遗传性疾病。临床表现常包括骨折,骨坏死(尤其是颌骨或上颌骨),骨髓炎,失明,和/或骨髓衰竭。ADO通常是由氯化物通道7基因(CLCN7)中的杂合错义变体引起的,这些变体通过显性负机制引起疾病。T细胞免疫调节因子1基因(TCIRG1)的变异体通常在常染色体隐性遗传性石骨症中被发现,但仅在一名ADO患者中被报道。
方法:在这里,我们报告了3个具有单个杂合错义变体的家族成员(p。Gly579Arg)在TCIRG1中具有与ADO一致的表型。五个蛋白质预测程序中的三个表明该变体可能抑制TCIRG1的功能。
结论:这是由TCIRG1变体引起的成人ADO的首次描述。类似于CLCN7突变的ADO家族,TCIRG1中的这种变体导致明显的表型变异性,两名受试者患有严重疾病,第三名患有非常轻微的疾病。该家族报告暗示TCIRG1错义突变是ADO的原因,并证明ADO中明显的表型变异性可能扩展到由TCIRG1错义突变引起的疾病。
BACKGROUND: Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T-cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in 1 patient with ADO.
METHODS: Here, we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of 5 protein prediction programs suggest this variant likely inhibits the function of TCIRG1.
CONCLUSIONS: This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with 2 subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.