TY - JOUR
T1 - Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis
AU - Jönsson, Åsa Lina M.
AU - Bendstrup, Elisabeth
AU - Mogensen, Susie
AU - Kopras, Elizabeth J.
AU - McCormack, Francis X.
AU - Campo, Ilaria
AU - Mariani, Francesca
AU - Escribano-Montaner, Amparo
AU - Holm, Are M.
AU - Martinez-Colls, Maria Del Mar
AU - Pintos-Morell, Guillem
AU - Taillé, Camille
AU - Crestani, Bruno
AU - Hilberg, Ole
AU - Hvarregaard Christensen, Jane
AU - Simonsen, Ulf
PY - 2020/2/1
Y1 - 2020/2/1
N2 - BACKGROUND: Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 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 SLC34A2 has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists. METHODS: We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 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. RESULTS: We identified eight novel allelic variants of SLC34A2 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. CONCLUSIONS: Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 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.
AB - BACKGROUND: Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 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 SLC34A2 has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists. METHODS: We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 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. RESULTS: We identified eight novel allelic variants of SLC34A2 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. CONCLUSIONS: Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 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.
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U2 - 10.1183/13993003.00806-2019
DO - 10.1183/13993003.00806-2019
M3 - Article
C2 - 31831582
AN - SCOPUS:85080827318
VL - 55
JO - European Respiratory Journal
JF - European Respiratory Journal
SN - 0903-1936
IS - 2
ER -