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, 25, 7634-7644

Identification of Five Novel Mutations Causing Rare Lysosomal Storage Diseases

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Case Reports

Identification of Five Novel Mutations Causing Rare Lysosomal Storage Diseases

Chenxi Yang et al. Med Sci Monit.

Abstract

BACKGROUND Lysosomal storage diseases (LSDs), a group of rare inherited metabolic disorders, result from specific lysosomal proteins deficiencies in the degradation of biomacromolecule, including over 70 different diseases, most of which are autosomal recessive. LSDs are multisystem disorders, and the clinical manifestations are usually broad and severe, involving the skeletal system, central nervous system (CNS), cardiovascular system, etc. Besides, patients with some subtypes of LSD have distinctive facial features. MATERIAL AND METHODS We performed next generation sequencing on 4 suspected mucopolysaccharidosis (MPS) cases to determine the genetic causes of the disease. By in vitro molecular cell assay, such as real-time polymerase chain reaction (RT-PCR) and western blot, we tested the pathogenicity of candidate variants. RESULTS We detected 5 novel mutations in 4 patients. The mutations were: c.211_214del and c.1270C>T in GUSB; c.1284+1C>A and c.2404C>T in GNPTAB; and c.717C>A in FUCA1). We identified a rare mucopolysaccharidosis VII patient, a rare fucosidosis patient, and 2 rare mucolipidosis II patients, one of which was an atypical patient. We also present a new pathogenic conjecture about a small deletion in GUSB. CONCLUSIONS Our study described rare diseases in Chinese patients and our results enrich the phenotype spectrum of related diseases, as well as mutation spectrum of related genes, which might be significant for clinical disease diagnosis and prenatal diagnosis.

Conflict of interest statement

Conflicts of interest

None.

Figures

Figure 1
Figure 1
The pathogenic of mutation c.211_214delTCAG in GUSB. (A) Amplification results show that Patient 1 and the control both had 3 transcripts (NM_000181, NM_001293104, NM_001293105), transcript variant 3 skipped exon 3, and transcript variant 4 skipped exon 3 and 4, but Patient 1’s 739 bp bands became lighter, as well as 554 bp and 411 bp bands were always brighter than the control’s. Schematic diagram shows the pattern of each transcript, the red block represents 5′-UTR. (B) The results of quantitative real-time polymerase chain reaction results of Patient 1 with small deletion mutation and the 2 normal controls. (BI) GUSB total mRNA levels were nearly 70% lower in Patient I than in normal controls (** P=0.0024). (BII) The mRNA level of product of transcript variant 1 (*** P=0.0003) was nearly 90% lower in Patient I than in normal controls, but the (BIII, BIV) mRNA levels of products of transcript variant 3 (** P=0.0016) and transcript variant 4 (** P=0.0012) remained over 40% and even 70% compared with controls. (C) Patient 1 presented typical MPS skeletal malformation: lumbar scoliosis, limbs length discrepancy, and carpal dysplasia.
Figure 2
Figure 2
The pathogenic of mutation c.717C>A in FUCA1. (A) The pedigree of Patient 2, the arrow points out proband. (B) Quantitative real-time polymerase chain reaction results of Patient 2, his parents, and normal control: FUCA1 mRNA levels were nearly 90% and 50% lower in Patient 2 and in his parents, respectively, than in normal controls (Patient 2: **** P<0.0001; Father and Mother: **** P<0.0001). (C) The western blot result of patient, mutation carrier, and normal control show that mutation c.717C>A affected protein expression. (D, E) The atypical phenotype of Patient 2 with fucosidosis. (D) Patient 2 has mild scoliosis. There was no observable abnormal presentation in dermal system. (E) Facial features mainly present as thick lips.
Figure 3
Figure 3
The atypical phenotype of Patient 3 with mucolipidosis II. (A, B) Patient 3 had low nasal bridge, broad nasal tip, long philtrum, arched eyebrow and abnormal auricle, besides skin was white and smooth. (C, D) Patient 3’s skeletal abnormalities included long fingers and long toes, which is rare in mucolipidosis II patients. (E) Quantitative real-time polymerase chain reaction results of Patient 3 with mutation c.2404C>T and normal control. GNPTAB mRNA levels were nearly 80% lower in Patient 3 than in normal controls (Patient 3: *** P=0.0008)
Figure 4
Figure 4
Real-time polymerase chain reaction results of mutation c.1284+1G>T in GNPTAB. (A) Amplification results shows that Patient 4 had additional amplification product compared with control, the 630 bp band represents the normal products, the 459 bp band represents the deletion of 1 exon. (B) Sanger sequencing results of cDNA product in Patient 4 compared with control shows the additional amplification product skip the exon 10. (C) Schematic diagram showing the pattern of exon skipping in Patient 4.

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