Figure 1. Identification of MBTPS1 compound heterozygote variants in a patient with skeletal dysplasia and elevated circulating levels of lysosomal enzymes.

(A) The patient exhibits skeletal dysplasia with kyphoscoliosis (I) and skeletal dysplasia with dysmorphic facial features, with large ears and pectus carinatum (II). (B) Serum lysosomal enzyme activities. (C) DNA sequences of MBTPS1 exon 3 and exon 9. Letters and numbers in red indicate mutated residues and sites in the S1P protein sequence. (D) Pedigree of the family. The black circle indicates the patient; half-black square or circles indicate heterozygotes. (E) Relative MBTPS1 expression in patient B cells by qRT-PCR normalized with control B cells. A forward primer designed in exon 19 and a reverse primer designed in exon 21 of MBTPS1 were used. Mean ± SEM; n = 3, *P < 0.01, Student’s t test. Patient cells exhibited 20% MBTPS1 expression compared with irrelevant control cells. (F) MBTPS1 cDNA sequence. The dashed box indicates an aberrant transcript. (G) Diagram showing that the maternal variant creates an alternative splice donor site, resulting in the 41-bp deletion in exon 9. The asterisk indicates the premature termination created by alternative splicing causing the 41-bp deletion in exon 9. (H) Schematic domain of S1P in the patient. Green, catalytic triad; red, mutated residues. SS, signal sequence; TM, transmembrane domain; CP, cytoplasmic domain. The three different S1P variants are expressed in the patient.