Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation.

由于异常的表面活性剂生物发生而引起的新生儿间质性肺疾病在人类中很少见，也从未被报道为动物的自发性疾病。我们在这里描述了一种新的肺疾病，在大狗（AT）犬中，其临床症状和病理与人类表面活性剂缺乏症的最严重新生儿形式相似。致命的低氧呼吸窘迫和衰竭发生在受影响的幼犬生命的头几天或几周内。受影响的肺部的透射电子显微镜显示，肺泡上皮II型（AECII）细胞中的层状体（LBs）的形成中止了成熟。分泌的细胞器很小，含有较少的薄片，通常与被偶尔破坏的共同限制膜包围的小囊泡结合在一起。LAMP3是AECII细胞中细胞质表面活性剂细胞器的一种限制性膜蛋白。取代位于与保守的二硫键相邻的LAMP结构域中。总而言之，这项研究描述了一种新的犬间质性肺疾病，鉴定了人类表面活性剂功能障碍的新候选基因，并对LAMP3在LB形成过程中的重要作用带来了重要见解。