Jönsson Åsa Lina M, Bendstrup Elisabeth, Mogensen Susie, Kopras Elizabeth J, McCormack Francis X, Campo Ilaria, Mariani Francesca, Escribano-Montaner Amparo, Holm Are M, Martinez-Colls Maria Del Mar, Pintos-Morell Guillem, Taillé Camille, Crestani Bruno, Hilberg Ole, Hvarregaard Christensen Jane, Simonsen Ulf
Dept of Biomedicine, Aarhus University, Aarhus, Denmark
Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.
Eur Respir J. 2020 Feb 27;55(2). doi: 10.1183/13993003.00806-2019. Print 2020 Feb.
Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists.
We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein.
We identified eight novel allelic variants of in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity.
Our findings support a significant role for in PAM and expand the variant spectrum of the disease. Thus, variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.
肺泡微石症（PAM）由 基因的遗传变异引起，该基因编码钠依赖性磷酸盐转运蛋白2B（NaPi-2b）。PAM的特征是磷酸钙结石（微石）在肺泡中沉积，导致肺功能障碍。 基因的变异谱尚未得到充分研究，目前尚不清楚是否存在基因型-表型相关性。
我们收集了14例PAM患者及其4名亲属的DNA，并通过直接DNA测序分析了 基因的编码区。为了确定表型特征，收集了临床数据，并根据蛋白质内的类型和定位为每个变异创建了严重程度评分。
我们在14例PAM患者中鉴定出8种新的 基因等位变异。其中4种为无义变异，3种为错义变异，1种为剪接位点变异。1例患者对两种不同变异呈杂合状态，所有其他患者均为纯合子。4例患者无症状，10例患者有症状。疾病的严重程度与变异的严重程度相关。
我们的研究结果支持 基因在PAM中起重要作用，并扩展了该疾病的变异谱。因此，在所有患者中均检测到 基因变异，并发现了8种新的等位变异。发现疾病严重程度与变异严重程度之间存在关联；然而，这需要在更大的患者群体中进行研究。
