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ATP6V0A2-Related Cutis Laxa

Synonym: Autosomal Recessive Cutis Laxa Type 2A

, MD, PhD, , MD, and , MD, PhD.

Author Information
, MD, PhD
Centre de génétique humaine
Université de Franche-Comté
Besançon, France
, MD
Seattle Children's Research Institute
Seattle, Washington
, MD, PhD
Institut für Medizinische Genetik
Charité Universitätsmedizin
Berlin, Germany

Initial Posting: ; Last Revision: May 10, 2011.

Summary

Disease characteristics. ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end. Affected individuals have furrowing of the skin of the whole body that improves with time. They may have other evidence of a generalized connective disorder, including enlarged anterior fontanelle in infancy, congenital dislocation of the hips, inguinal hernias, and high myopia. In most (not all) affected individuals, cortical and cerebellar malformations are present and are associated with severe developmental delays, seizures, and neurologic regression.

Diagnosis/testing. Diagnosis is based on characteristic findings on clinical examination of the skin, serum sialotransferrin isoelectric focusing (IEF), serum apolipoprotein C III IEF, and molecular genetic testing of ATP6V0A2, the only gene known to be associated with this disorder.

Management. Treatment of manifestations: Antiepileptic drugs (AEDs), repair of inguinal hernia(s), routine management of hip dislocation, and psychological help as needed for self-image issues.

Surveillance: Annual ophthalmologic examination.

Other: It is best to avoid plastic surgery in infancy or childhood because the skin findings tend to improve with age.

Genetic counseling. ATP6V0A2-related cutis laxa is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family.

GeneReview Scope

ATP6V0A2-Related Cutis Laxa: Included Disorders
  • Debré-type cutis laxa
  • Wrinkly skin syndrome

Diagnosis

Clinical Diagnosis

ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A), spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end.

ATP6V0A2-related cutis laxa is diagnosed in individuals with the characteristic signs of cutis laxa:

  • Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin
  • Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features
  • Skin that when extended does not display hyperelasticity (as in the Ehlers-Danlos syndromes) but rather keeps its consistency

Other evidence of a generalized connective tissue disorder

  • Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age one year)
  • Congenital dislocation of the hips
  • Inguinal hernias
  • High myopia
  • Bruch’s membrane rupture

Central nervous system (CNS) abnormalities. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. 

  • Cortical malformation. Abnormally thick (5-10 mm) cortex has subtle vertical streaks that appear smooth in some areas and irregular in others, resembling either lissencephaly or polymicrogyria, particularly the cortical malformation of GPR56-associated fronto-parietal cobblestone-like cortical malformation (see Polymicrogyria Overview) or muscle-eye-brain (MEB) disease (see Congenital Muscular Dystrophy Overview), except that white matter changes are more prominent in the two latter conditions.

    This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes them from true polymicrogyria.
  • Cerebellar malformation ranges from mild cerebellar vermis hypoplasia to classic Dandy-Walker malformation, including severe hypoplasia and upward rotation of the vermis, cystic enlargement of the fourth ventricle, and enlarged posterior fossa.

Testing

Serum sialotransferrin isoelectric focusing (IEF). Findings in ATP6V0A2-related cutis laxa:

  • Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues
  • Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of:
    • Disialotransferrin: 2.5%-9.8%
    • Trisialotransferrin: 3.4%-13.7%

These findings, which are also observed in type 2 congenital disorder of glycosylation (CDG type 2), support the diagnosis of ATP6V0A2-related cutis laxa [Morava et al 2005, Wopereis et al 2005, Morava et al 2008, Guillard et al 2009] (see Congenital Disorders of Glycosylation Overview).

Note: In the authors’ experience, all probands had a CDG type 2 sialotransferrin IEF pattern; however, it has been observed that infants may have a normal transferrin isofocusing profile in the first months of life, but develop the typical transferrin abnormality later on. In these infants, the apolipoprotein C-III isofocusing was already abnormal in the first months of life [Morava et al 2005, Wopereis et al 2005].

Serum apolipoprotein C III isoelectric focusing (IEF) reveals the following changes of altered O-glycosylation:

  • Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues
  • Increased amounts of monosialotransferrin. Normal ranges depend on age. In adults: monosialotransferrin: 43%-69%; disialotransferrin: 23%-50%.

Abnormal O-glycosylation is supportive of the diagnosis, but a normal or inconclusive result does eliminate the possibility of ATP6V0A2-related cutis laxa. In the authors’ experience, comparing the findings in the parents with those of the index case is most helpful in identifying the reduction of the main band.

Skin biopsy with orcein staining

  • Light microscopy is normal.
  • Electron microscopy (EM). Rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities.

    Note: EM studies require a high level of expertise and are only available in specialized centers.

Molecular Genetic Testing

Genes. ATP6V0A2 is the only gene associated with ATP6V0A2-related cutis laxa.

Clinical testing

  • Sequence analysis. Thus far diagnosis of ATP6V0A2-related cutis laxa has been confirmed in no more than 55 individuals by ATP6V0A2 sequencing.

    In individuals with cutis laxa and a clear CDG type 2 sialotransferrin IEF pattern, mutation detection rate is high; however, it is possible that in a subset of affected individuals, exon or whole-gene deletions (which cannot be detected by sequence analysis) are present.

    When parental consanguinity is present, detection of homozygosity for ATP6V0A2 polymorphic markers may provide an incentive for full-sequence analysis of the gene.
  • Deletion/duplication analysis. Hucthagowder et al [2009] identified deletion of exon 16 in four unrelated individuals of Middle Eastern origin in their cohort of 17 affected individuals from 16 families.

Table 1. Summary of Molecular Genetic Testing Used in ATP6V0A2-Related Cutis Laxa

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ATP6V0A2Sequence analysis 4Sequence variantsUnknown
Deletion/duplication analysis 5(Multi)exon or whole-gene deletion/duplication

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

Testing Strategy

Confirming/establishing the diagnosis in a proband. The diagnosis of ATP6V0A2-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have two disease-causing mutations in ATP6V0A2.

Abnormal results on biochemical studies (sialotransferrin IEF and apolipoprotein CIII IEF) and skin biopsy increase the probability of finding an ATP6V0A2 mutation.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

ATP6V0A2-related cutis laxa spans a phenotypic spectrum that includes Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined.

Debré-type cutis laxa. Affected children have more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children with wrinkly skin syndrome. In ATP6V0A2-related cutis laxa the skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some.

At birth, hypotonia, over-folded skin, and distinctive facial features are present. Enlarged fontanelles are invariably present in infants with Debré-type cutis laxa. During childhood, facial features and the thick or coarse hair may become quite distinctive.

Nearly all affected children described to date have had delayed developmental milestones and intellectual disability. Most have borderline microcephaly with head circumference in the range of -2 to -3 standard deviations. Despite delays in developmental milestones and language, affected children are said to be cheerful and outgoing.

Many children have a degenerative course including cognitive decline that begins about the end of the first decade. Generalized or partial complex seizures begin between ages eight and 12 years. Six of eight children fulfilling diagnostic criteria for Debré-type cutis laxa developed seizures by their mid-teens.

Note: By contrast, a lower rate of seizures was observed in a cohort of children with autosomal cutis laxa (regardless of accompanying signs and symptoms) and abnormal IEF [Morava et al 2005, Morava et al 2008] and a cohort of children from Oman [Rajab et al 2008]. An explanation could be age-related bias of ascertainment, given that most children in these two cohorts were young.

Neurologic regression (with or without seizures) can include spasticity and cerebellar signs and symptoms (ataxia, slurred speech). Some adolescents become wheelchair bound.

High myopia (> -5 diopters) has been observed in the majority of affected individuals. One Portuguese individual had an unclassified corneal dysplasia requiring engraftment; a Belgian individual had unilateral rupture of Bruch’s membrane rupture. Strabismus has been observed in nearly half of the patients.

A unique individual with mild brain dysgenesis and compound heterozygosity for ATP6V0A2 mutations had a normal IQ with no history of seizures, and was doing well in mainstream school at age 15 years [Van Maldergem et al 2008].

Pulmonary emphysema does not occur.

Wrinkly skin syndrome (WSS) includes many features of Debré-type cutis laxa but is milder [Gazit et al 1973]. Usually, affected individuals have only mild developmental delay without subsequent neurodegeneration. The skin shows tighter wrinkles and the changes in facial features are milder [Al-Gazali et al 2001]. In one of the four WSS families from Oman described recently, the father of an index patient appeared to be affected as well, as determined by molecular genetic testing after subtle signs of WSS were noted during clinical examination [Rajab et al 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Prevalence

The prevalence of all types of cutis laxa is 1:4,000,000 according to Rhone-Alpes Eurocat registry [E Robert, personal observation].

Differential Diagnosis

Other disorders characterized by cutis laxa are summarized in Table 2.

FBLN5-related cutis laxa (ARCL1A) is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death. Inheritance is autosomal recessive.

EFEMP2 (FBLN4)-related cutis laxa (ARCL1B). Based on reports of two affected individuals, EFEMP2-related cutis laxa appears to comprise arachnodactyly and arterial tortuosity with a predisposition for aneurysms and dissections [Hucthagowder et al 2006, Dasouki et al 2007]. The cutis laxa and emphysema are similar in EFEMP2- or FBLN5-related cutis laxa; however, to date the diaphragmatic changes and arterial aneurysms appear to be more predominant in EFEMP2-related cutis laxa. Inheritance is autosomal recessive.

ELN-related cutis laxa (ADCL) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN mutations can also have aortic aneurysms that require aortic root replacement or lead to aortic rupture in early adulthood. The aortic pathology of these aneurysms is indistinguishable from that of Marfan syndrome. It remains to be seen whether ELN is mutated in persons with thoracic aortic aneurysms and aortic dissections (TAAD) [Urban et al 2005] (see Thoracic Aortic Aneurysms and Aortic Dissections). Inheritance is autosomal dominant.

Gerodermia osteodysplastica (GO). Onset occurs in infancy or early childhood (for review, see Nanda et al [2008]). Children appear older than their age because of sagging cheeks and jaw hypoplasia. Skin wrinkling is less severe and is confined to the dorsum of the hands and feet and to the abdomen when in the sitting position. A generalized connective tissue weakness leads to frequent hip dislocation and hernias; however, GO can be distinguished from other types of cutis laxa by the presence of osteopenia/osteoporosis and fractures, most commonly vertebral compression fractures, but also fractures of the long bones. Mental development is in the normal range. In contrast to Debré-type cutis laxa, fontanelle size and closure are normal; positioning of the palpebral fissures is normal; and disease manifestations do not become milder with age. Mutations in GORAB (formerly SCYL1BP1) are causative [Hennies et al 2008]. A GO-like phenotype, but in most cases with intellectual disability, can be caused by mutations in PYCR1 (see below).

De Barsy syndrome. Characterized by a progeroid appearance, pre- and postnatal growth retardation, moderate to severe intellectual disability, corneal clouding or cataracts, and generalized cutis laxa [Guerra et al 2004]. The progeroid appearance is not caused by skin sagging, but rather by a hypoplasia of the dermis. Joint hyperlaxity, pseudo-athetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive. In a number of individuals who received this diagnosis mutations in PYCR1 were identified [Reversade et al 2009] (see following).

PYCR1-related cutis laxa (ARCL2B). Mutations in PYCR1 cause a phenotype which shares many similarities with GO, with wrinkly skin syndrome, and with De Barsy syndrome. Affected individuals have a common facial gestalt with triangular face, hypomimia, large everted ears and a cutis laxa more pronounced in extremities. About 95% of affected individuals show intellectual disability. Hypoplasia of the corpus callosum is common. The protein is involved in proline biosynthesis in mitochondria [Reversade et al 2009].

ALDH18A1-related cutis laxa. A syndrome of IUGR, cataracts, postnatal growth failure and developmental delay with cutis laxa has been described in two pedigrees. Joint hyperlaxity is apparently a common feature. This autosomal recessive syndrome falls within de Barsy syndrome spectrum. It is associated with mutations in ALDH18A1, previously known as P5CS, encoding delta-1-pyrroline-5-carboxylate synthase (P5CS) [Baumgartner et al 2000, Baumgartner et al 2005, Bicknell et al 2008].

LTBP4-related cutis laxa. Urban et al [2009] described four patients with cutis laxa, a phenotype resembling pulmonary associated cutis laxa (EFEMP2- and FBLN5-related). A characteristic of this subtype is the severity of associated malformations, including major congenital heart disease, severe pulmonary hypertension, thought to be the consequence of pulmonary arteries stenosis, diaphragmatic hernia and multiple bladder diverticulae with vesicoureteral reflux were causative of life-threatening complications and short life span. The authors observed prolonged survival in a girl who ultimately died of multiple brain abscesses at age 14 years.

Telecanthus, epicanthus, and a droopy facial appearance are very similar to that seen in EFEMP2- and FBLN5-related CL

LTBP4 encodes a protein which plays a role in assembly of elastin fibres.

RIN2-related cutis laxa. Mutations in RIN2 cause MACS syndrome (macrocephaly, alopecia, cutis laxa, scoliosis), displaying a very characteristic facial gestalt [Basel-Vanagaite et al 2009]. Cutis laxa is mild and mostly manifests as redundant skin at the face. Mild intellectual disability is only present in some affected individuals.

Table 2. Disorders to Consider in the Differential Diagnosis of Cutis Laxa

Disease Name Gene SymbolOMIMInheritanceClinical Findings
Cutis LaxaEmphysemaAneurysmsDevelopmental Delay
ALDH18A1-related cutis laxaALDH18A1 219150AR+++
FBLN5-related cutis laxaFBLN5219100AR ++++++
EFEMP2-related cutis laxaEFEMP2 (FBLN4)614437AR+++++++
ARCL2AATP6V0A2219200AR++++
ADCLELN or FBLN5123700
614434
AD+++
GOGORAB231070AR++
De Barsy syndrome PYCR1614438AR++++
ARCL2BPYCR1612940AR+_+++
LTBP4-related cutis laxaLTBP4613177AR+++++
RIN2-related cutis laxaRIN2613075AR++/–

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ATP6V0A2-related cutis laxa, the following evaluations are recommended:

  • Ortolani sign for detection of hip dislocation. Hip ultrasound examination as needed based on clinical findings.
  • Pelvic x-ray (one time only) to identify hip dysplasia in the event that hip dislocation has not been treated properly.
  • Assessment for inguinal hernias
  • Ophthalmologic examination, including refraction (for myopia), slit-lamp examination, fundus examination. Note: Slit-lamp examination allows diagnosis of corneal dysplasia, which was present in one individual.
  • Brain MRI
  • EEG if seizures are suspected
  • Echocardiogram to look for evidence of floppy valves or more severe valvular dysplasia that can often be observed in a connective tissue disorder

Treatment of Manifestations

The following are appropriate:

  • Repair of inguinal hernia(s)
  • Routine management of hip dislocation
  • Routine management of refractive errors
  • Antiepileptic drugs (AEDs): valproate. Because treatment with valproate is often unsuccessful, carbamazepine can serve as a second-line drug and levetiracetam as a third-line drug. Or a combination of AEDs can be used.
  • Psychological help as needed for self-image issues

Surveillance

Perform annual ophthalmologic examination, including refraction for evidence of myopia (which can be progressive) and fundus examination to inspect Bruch’s membrane.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ATP6V0A2-related cutis laxa is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • To date, no individual with Debré-type cutis laxa has been known to reproduce.
  • Individuals with wrinkled skin type cutis laxa do reproduce; their offspring are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ATP6V0A2-Related Cutis Laxa: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ATP6V0A2-Related Cutis Laxa (View All in OMIM)

219200CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIA; ARCL2A
278250WRINKLY SKIN SYNDROME; WSS
611716ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A2; ATP6V0A2

Molecular Genetic Pathogenesis

Independent of the underlying molecular pathophysiology, all types of cutis laxa are characterized by alterations of elastic fibers, not collagen. In ultrastructural investigations elastic fibers are reduced in number and often appear fragmented.

The assembly of elastic fibers, a complex mechanism, takes place in the extracellular space. According to the currently accepted model, microfibrillar proteins like the fibrillins first form a lattice with fibulins into which secreted tropoelastin is deposited and further processed [Kielty 2006]. Enzymes necessary for the conversion of tropoelastin into elastin are the lysyl oxidases, which form covalent crosslinks between elastin molecules. Elastic fibers not only increase the elasticity of the extracellular matrix, but also influence its architecture and regulate TGFβ-signaling.

A complex mechanism underlies autosomal recessive cutis laxa Debré-type/ARCL2A. In contrast to ARCL1, the loss-of-function mutations do not affect an extracellular matrix protein, but a subunit of a v-type H+-ATPase that resides in endosomes as well as in the Golgi compartment [Hurtado-Lorenzo et al 2006, Pietrement et al 2006]. Proton pumps are universally expressed and allow pH regulation in the extracellular space and in many subcellular compartments [Forgac 2007]. In addition, there are indications that a subunit of the proton pump complex is directly involved in vesicle fusion [Peters et al 2001]. Evidence that suggests that a defect of the secretory pathway is the basis of the elastic fiber defect in ARCL2A is the following:

  • Affected individuals show a glycosylation defect, which can be detected by IEF of serum transferrin [Kornak et al 2008].
  • Cells from affected individuals display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.

Gene structure. ATP6V0A2 comprises 20 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Only two non-synonymous coding normal variants are found in ATP6V0A2 (see Table 3): rs7969410 (p.Arg685Gln) in exon 16 and rs17883456 (p.Ala813Val) in exon 19. Both have a frequency of approximately 2%.

Pathogenic allelic variants. ATP6V0A2 mutations are scattered over the entire coding sequence. Of the ten mutations described to date, four are splice-site mutations, three are nonsense mutations, and three are frameshift mutations [Kornak et al 2008]. The most 5’ residue affected is p.Arg63Ter and the most 3’ mutation is p.Gln765Ter. Both mutations have been found in several individuals [Author, unpublished observation].

Table 3. Selected ATP6V0A2 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Benignc.2302G>Ap.Arg685Gln NM_012463​.2
NP_036595​.2
c.2686C>Tp.Alal813Val
Pathogenicc.187C>Tp.Arg63Ter
c.294+1G>A--
c.353_354delTGp.Lys117fsTer144
c.732-2A>G--
c.839delCp.Thr280fsTer285
c.1324G>Tp.Glu442Ter
c.1929delAp.Thr643fsTer683
c.2176-2_3delCA--
c.2293C>Tp.Gln765Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. ATP6V0A2 encodes the a2 subunit of the v-type H+-ATPase complex. It is a membrane protein with eight to nine transmembrane helices that anchor the complex to the membrane and are directly involved in proton translocation [Marshansky 2007]. The protein resides in the Golgi compartment and in endosomes where it adjusts the luminal pH by transport of protons from the cytosol.

Abnormal gene product. Most ATP6V0A2 mutations lead to severe protein truncation that most likely destabilizes the protein, leading to a loss of function [Kornak et al 2008].

References

Literature Cited

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Chapter Notes

Acknowledgments

We thank the families for their continuing participation.

Revision History

  • 10 May 2011 (cd) Revision: deletion/duplication analysis available clinically; ALDH18A1 -related cutis laxa added to differential diagnosis
  • 23 September 2010 (me) Comprehensive update posted live
  • 19 March 2009 (me) Review posted live
  • 10 September 2008 (lvm) Original submission
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