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ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA

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ABSTRACT

Patients with ARCL-IIA harbor mutations in ATP6V0A2 that codes for an organelle proton pump. The ARCL-IIA syndrome characteristically presents a combined glycosylation defect affecting N-linked and O-linked glycosylations, differentiating it from other cutis laxa syndromes and classifying it as a Congenital Disorder of Glycosylation (ATP6V0A2-CDG). We studied two Mexican Mestizo patients with a clinical phenotype corresponding to an ARCL-IIA syndrome. Both patients presented abnormal transferrin (N-linked) glycosylation but Patient 1 had a normal ApoCIII (O-linked) glycosylation profile. Mutational screening of ATP6V0A2 using cDNA and genomic DNA revealed in Patient 1 a previously reported homozygous nonsense mutation c.187C>T (p.R63X) associated with a novel clinical finding of a VSD. In Patient 2 we found a homozygous c.2293C>T (p.Q765X) mutation that had been previously reported but found that it also altered RNA processing generating a novel transcript not previously identified (r.2176_2293del; p.F726Sfs*10). This is the first report to describe Mestizo patients with molecular diagnosis of ARCL-IIA/ATP6V0A2-CDG and to establish that their mutations are the first to be found in patients from different regions of the world and with different genetic backgrounds.

No MeSH data available.


IEF of serum transferrin showing an abnormal type II profile for both patients. C, control sample; P1, Patient 1; P2, Patient 2. Numbers in the edge correspond to the number of sialic acids in the transferrin isoforms.
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f0010: IEF of serum transferrin showing an abnormal type II profile for both patients. C, control sample; P1, Patient 1; P2, Patient 2. Numbers in the edge correspond to the number of sialic acids in the transferrin isoforms.

Mentions: To further confirm if this patient had the characteristic hypoglycosylation seen in ATP6V0A2-CDG, serum transferrin glycosylation (N-glycoprotein) was analyzed by IEF and revealed an abnormal type II profile (Fig. 2) which indicates truncated glycans of transferrin and points to a Golgi compartment disturbance [11]. Subsequently, transferrin and Apolipoprotein CIII (ApoCIII, O-glycoprotein) were profiled by mass spectrometry, confirming the hypoglycosylation of serum transferrin but revealing normal glycosylation of serum ApoCIII (Fig. 3). Although ATP6V0A2-CDG patients commonly have both abnormal transferrin and ApoCIII hypoglycosylation [1], [7], the clinical phenotype and transferrin hypoglycosylation hinted to mutations in ATP6V0A2. The mutational analysis of ATP6V0A2 using patient cDNA revealed a single ATP6V0A2 transcript with a nonsense mutation in exon 2 that codes for a premature stop codon (c.187C>T; p.R63X). Sanger sequencing on patient genomic DNA confirmed that the c.187C>T was homozygous and analysis of familial DNA confirmed that it was inherited in a recessive fashion (Fig. 4A). Screening of parental gDNA confirmed the recessive transmission. This mutation was previously reported, also in a homozygous state, in only two Turkish patients with ARCL-IIA [1], [12].


ATP6V0A2 mutations present in two Mexican Mestizo children with an autosomal recessive cutis laxa syndrome type IIA
IEF of serum transferrin showing an abnormal type II profile for both patients. C, control sample; P1, Patient 1; P2, Patient 2. Numbers in the edge correspond to the number of sialic acids in the transferrin isoforms.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121299&req=5

f0010: IEF of serum transferrin showing an abnormal type II profile for both patients. C, control sample; P1, Patient 1; P2, Patient 2. Numbers in the edge correspond to the number of sialic acids in the transferrin isoforms.
Mentions: To further confirm if this patient had the characteristic hypoglycosylation seen in ATP6V0A2-CDG, serum transferrin glycosylation (N-glycoprotein) was analyzed by IEF and revealed an abnormal type II profile (Fig. 2) which indicates truncated glycans of transferrin and points to a Golgi compartment disturbance [11]. Subsequently, transferrin and Apolipoprotein CIII (ApoCIII, O-glycoprotein) were profiled by mass spectrometry, confirming the hypoglycosylation of serum transferrin but revealing normal glycosylation of serum ApoCIII (Fig. 3). Although ATP6V0A2-CDG patients commonly have both abnormal transferrin and ApoCIII hypoglycosylation [1], [7], the clinical phenotype and transferrin hypoglycosylation hinted to mutations in ATP6V0A2. The mutational analysis of ATP6V0A2 using patient cDNA revealed a single ATP6V0A2 transcript with a nonsense mutation in exon 2 that codes for a premature stop codon (c.187C>T; p.R63X). Sanger sequencing on patient genomic DNA confirmed that the c.187C>T was homozygous and analysis of familial DNA confirmed that it was inherited in a recessive fashion (Fig. 4A). Screening of parental gDNA confirmed the recessive transmission. This mutation was previously reported, also in a homozygous state, in only two Turkish patients with ARCL-IIA [1], [12].

View Article: PubMed Central - PubMed

ABSTRACT

Patients with ARCL-IIA harbor mutations in ATP6V0A2 that codes for an organelle proton pump. The ARCL-IIA syndrome characteristically presents a combined glycosylation defect affecting N-linked and O-linked glycosylations, differentiating it from other cutis laxa syndromes and classifying it as a Congenital Disorder of Glycosylation (ATP6V0A2-CDG). We studied two Mexican Mestizo patients with a clinical phenotype corresponding to an ARCL-IIA syndrome. Both patients presented abnormal transferrin (N-linked) glycosylation but Patient 1 had a normal ApoCIII (O-linked) glycosylation profile. Mutational screening of ATP6V0A2 using cDNA and genomic DNA revealed in Patient 1 a previously reported homozygous nonsense mutation c.187C>T (p.R63X) associated with a novel clinical finding of a VSD. In Patient 2 we found a homozygous c.2293C>T (p.Q765X) mutation that had been previously reported but found that it also altered RNA processing generating a novel transcript not previously identified (r.2176_2293del; p.F726Sfs*10). This is the first report to describe Mestizo patients with molecular diagnosis of ARCL-IIA/ATP6V0A2-CDG and to establish that their mutations are the first to be found in patients from different regions of the world and with different genetic backgrounds.

No MeSH data available.