SLC34A2 gene compound heterozygous mutation identification in a patient with pulmonary alveolar microlithiasis and computational 3D protein structure prediction

Abstract

We recently diagnosed a patient with pulmonary alveolar microlithiasis (PAM). Because loss-of-function mutations of the SLC34A2 gene are responsible for the development of PAM, we sought to sequence the SLC34A2 gene of the patient and his direct relatives, with a purpose to identify mutations that caused the PAM of the patient as well as the carriers of his family. We found a novel compound heterozygous mutation of the SLC34A2 gene in this patient, which were the mutations of c.1363T > C (p. Y455H) in exon 12 and c.910A > T (p. K304X) in exon 8. Computational prediction of three-dimensional (3D) structures of the mutants revealed that the Y455H mutation resulted in a formation of irregular coils in the trans-membrane domain and the K304X mutation resulted in protein truncation. Our study suggested that sequencing of the SLC34A2 gene together with a computational prediction of the 3D structures of the mutated proteins may be useful in PAM diagnosis and prognosis.

Pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide

“…With the exception of the patient reported by WANG et al [27], the mutations were always in a homozygous state, highlighting the rarity of PAM. HUQUN et al [2] calculated that the frequency of a mutant allele in the general population is <0.008.…”

“…The most numerous groups were two families with six affected relatives [6,23], followed by two families with five patients [6,24] and five families with four cases [5,16,[25][26][27]. In accordance with the autosomal recessive inheritance, in almost all familial cases transmission was horizontal (online supplementary table E1).…”

“…The only exceptions are the mutations in exon 12 identified in two unrelated Danish patients by JÖNSSON et al [35] and in one patient described by WANG et al [27], and the homozygous mutation in exon 6 reported by MA et al [26]. In the Danish cases, the authors hypothesised that mutations resulted in the deletion of one of the four sequential threonine codons, altering protein structure and, presumably, function [35].…”

“…Regarding mutations, exon 8 and exon 12 are more commonly involved. In particular the c. 910A>T exon 8 mutation seems to be common and might be the screening target for Chinese patients [27,32,37]. Apart from these cases, no other recurrent mutations have been identified, indicating that the high prevalence of PAM disease in some populations (e.g.…”

“…In the Danish cases, the authors hypothesised that mutations resulted in the deletion of one of the four sequential threonine codons, altering protein structure and, presumably, function [35]. In the case described by WANG et al [27], computational prediction of three-dimensional structures of the mutants revealed that the c.1363T>C ( p. Y455H) mutation resulted in the formation of irregular coils in the transmembrane domain. Finally, the exon 6 mutation reported by MA et al [26] was considered the pathological factor on the basis of phenotypegenotype cosegregation in the family.…”