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ATP6V0A2-Related Cutis Laxa

Synonym: Autosomal Recessive Cutis Laxa Type 2A (ARCL2A)

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

Author Information

Initial Posting: ; Last Update: February 12, 2015.

Estimated reading time: 19 minutes


Clinical 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 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.


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.

Prevention of secondary complications: Treatment for bleeding disorder linked to coagulation factor deficiencies to prevent anemia.

Surveillance: Annual ophthalmologic examination.

Other: Plastic surgery in infancy or childhood is not advised, as 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 pathogenic variants have been identified in the family.

GeneReview Scope

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


Suggestive Findings

Diagnosis of ATP6V0A2-related cutis laxa, also known as autosomal recessive cutis laxa type 2A (ARCL2A) should be suspected in individuals with the following findings.

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 that also include prominent large nasal root, downslanted palpebral fissures, and delayed closure of the fontanelles
  • Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains 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 ADGRG1-associated fronto-parietal cobblestone-like cortical malformation (see Polymicrogyria Overview) or muscle-eye-brain (MEB) disease, 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 the disorder 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.
  • Corpus callosum is normal, in contrast to PYCR1-related cutis laxa, as underlined recently by a Dutch group [Gardeitchik et al 2014].

Laboratory test and skin biopsy findings

Serum sialotransferrin isoelectric focusing (IEF) reveals the following 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 not 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) shows 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.

Establishing the Diagnosis

The diagnosis of ATP6V0A2-related cutis laxa is established in a proband with the identification of biallelic pathogenic variants in ATP6V0A2 (see Table 1). Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of ATP6V0A2 is performed first and followed by deletion/duplication analysis if only one or no pathogenic variant is found.
  • Use of a multigene panel that includes ATP6V0A2 and other genes of interest (see Differential Diagnosis) may also be used. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes ATP6V0A2) has not confirmed a diagnosis in an individual with features of ATP6V0A2-related cutis laxa. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ATP6V0A2-Related Cutis Laxa

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
ATP6V0A2Sequence analysis 2>95% 3
Deletion/duplication analysis 4Unknown 5

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Thus far diagnosis of ATP6V0A2-related cutis laxa has been confirmed in more than 61 individuals by ATP6V0A2 sequencing. In individuals with cutis laxa and a clear CDG type 2 sialotransferrin IEF pattern, variant detection rate exceeds 95% [Gardeitchik et al 2014].


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


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.

Clinical Characteristics

Clinical Description

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. Children with Debré-type cutis laxa have more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children with wrinkly skin syndrome.

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, the characteristic facial features and thick or coarse hair may become quite pronounced. In ATP6V0A2-related cutis laxa the skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some [Greally et al 2014].

Developmental delay. 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 2-3 standard deviations below the mean. Despite delays in developmental milestones and language, affected children are said to be cheerful and outgoing.

Neurologic findings

  • Cognitive. Many children have a degenerative course including cognitive decline that begins about the end of the first decade.
  • Seizures. 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 two cohorts: one of children with ATP6V0A2-related cutis laxa (regardless of accompanying signs and symptoms) and abnormal IEF [Morava et al 2005, Morava et al 2008]; and the other 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. A unique individual with mild brain dysgenesis and compound heterozygosity for ATP6V0A2 pathogenic variants 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].

Ophthalmologic concerns. 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 patients.


  • Pulmonary emphysema does not occur.
  • Bleeding disorder linked to coagulation factor deficiencies may 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 families with WSS 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.


The prevalence of all types of cutis laxa is 1:4,000,000 according to Rhône-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; ADCL2) 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 usually autosomal recessive; autosomal dominant inheritance is possible.

EFEMP2-related cutis laxa (ARCL1B) is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems. Inheritance is autosomal recessive.

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.

ELN-related cutis laxa (ADCL1) (OMIM 123700) was historically considered a strictly cutaneous disorder without systemic involvement; however, it is now known that persons with ELN pathogenic variants 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]. Inheritance is autosomal dominant.

Gerodermia osteodysplastica (GO) (OMIM 231070). 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. Pathogenic variants in GORAB (formerly SCYL1BP1) are causative [Hennies et al 2008]. Inheritance is autosomal recessive. A GO-like phenotype, but in most cases with intellectual disability, can be caused by pathogenic variants in PYCR1 (see below).

De Barsy syndrome B (ARCL3B) (OMIM 614438) is 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, pathogenic variants in PYCR1 were identified [Reversade et al 2009] (see following).

PYCR1-related cutis laxa (ARCL2B; ARCL3B) (OMIM 612940, 614438). Pathogenic variants in PYCR1 cause a phenotype which shares many similarities with GO, wrinkly skin syndrome, and 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 have intellectual disability. Hypoplasia of the corpus callosum is common. The protein is involved in proline biosynthesis in mitochondria [Reversade et al 2009]. Inheritance is autosomal recessive.

ALDH18A1-related cutis laxa (ARCL3A) (OMIM 219150). 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 syndrome falls within de Barsy syndrome spectrum. It is associated with pathogenic variants 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]. Inheritance is autosomal recessive.

LTBP4-related cutis laxa (ARCL1C). Urban et al [2009] described four patients with 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 arterial 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.

A droopy facial appearance is very similar to that seen in EFEMP2- and FBLN5-related CL.

LTBP4 encodes a protein which plays a role in assembly of elastin fibers. Inheritance is autosomal recessive [Callewaert et al 2013].

RIN2-related cutis laxa. Pathogenic variants in RIN2 cause MACS syndrome (OMIM 613075) (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 facial skin. Mild intellectual disability is only present in some affected individuals. Inheritance is autosomal recessive.

Arterial tortuosity syndrome (ATS) is characterized by severe and widespread arterial tortuosity of the aorta and middle-sized arteries (with an increased risk of aneurysms and dissections) and focal and widespread stenosis which can involve the aorta and/or pulmonary arteries. The vascular findings occur in combination with soft/doughy skin and other evidence of a generalized connective tissue disorder including skeletal findings (scoliosis, pectus excavatum/carinatum, joint laxity, knee/elbow contractures, arachnodactyly, camptodactyly), inguinal/abdominal wall hernia, sliding hiatal or diaphragmatic hernia, hypotonia, and ocular involvement (myopia, keratoconus). Individuals may display a droopy facial appearance similar to that observed in other forms of cutis laxa [Karakurt et al 2012] and have a high palate with dental crowding.

Pathogenic variants in SLC2A10 are causative. Inheritance is autosomal recessive.

Lenz-Majewski syndrome (LMS) (OMIM 151050). Individuals with LMS display early cutis laxa followed by progressive thinning of the skin with prominent veins. Severe brachydactyly and a unique facial appearance with prominent eyes distinguish LMS in the early stages from other forms of cutis laxa [Sousa et al 2014]. The clinical course usually includes profound intellectual disability, very short stature, and progressive hyperostosis. Heterozygous pathogenic variants in PTDSS1 are causative. Inheritance is autosomal dominant.

Table 2.

Disorders to Consider in the Differential Diagnosis of Cutis Laxa

Disease NameGeneOMIMMOIClinical Findings
Cutis laxaEmphysemaAneurysmsDDBladder
ALDH18A1–related cutis laxaALDH18A1219150AR+--++-
FBLN5-related cutis laxaFBLN5219100AR++++++--++
EFEMP2-related cutis laxaEFEMP2 (FBLN4)614437AR+++++++--
ADCL1 or ADCL2ELN or FBLN5123700
De Barsy syndrome BPYCR1614438AR+--+++-
LTBP4-related cutis laxaLTBP4613177AR+++++++
RIN2-related cutis laxaRIN2613075AR+--+/-Unknown

ADCL = autosomal dominant cutis laxa; ARCL2A = the subject of this GeneReview; ARCL2B = PYCR1-related cutis laxa; ATS = arterial tortuosity syndrome; DD = developmental delay; GO = gerodermia osteodysplastica; LMS = Lenz-Majewski syndrome; MOI = mode of inheritance


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 (1x 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.
  • Baseline neurodevelopmental evaluation
  • 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
  • Evaluation for a bleeding disorder linked to coagulation factor deficiencies
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are appropriate:

  • Repair of inguinal hernia(s)
  • Routine management of hip dislocation
  • Routine management of refractive errors
  • Early education services and developmental therapies with later special education supports
  • 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

Prevention of Secondary Complications

Treat for bleeding disorder linked to coagulation factor deficiency to prevent anemia.


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

It is appropriate to test older and younger sibs for presence of the ATP6V0A2 pathogenic variants found in the proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

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

Therapies Under Investigation

Search in the US and in Europe 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 (i.e., carriers of one ATP6V0A2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 of an ATP6V0A2 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • To date, no individual with Debré-type cutis laxa has been known to reproduce.
  • Individuals with wrinkly skin type cutis laxa do reproduce; their offspring are obligate heterozygotes (carriers) for an ATP6V0A2 pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an ATP6V0A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ATP6V0A2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ATP6V0A2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ATP6V0A2-related cutis laxa are possible.


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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ATP6V0A212q24​.31V-type proton ATPase 116 kDa subunit a2ATP6V0A2 databaseATP6V0A2ATP6V0A2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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


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 pathogenic loss-of-function variants 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]. The following evidence suggests that a defect of the secretory pathway is the basis of the elastic fiber defect in ARCL2A:

  • 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.

Benign variants. Only two nonsynonymous coding normal variants are found in ATP6V0A2: rs7969410 (p.Arg685Gln) in exon 16 and rs17883456 (p.Ala813Val) in exon 19. Both have a frequency of approximately 2%.

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

Table 3.

Selected ATP6V0A2 Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences

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​ 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 pathogenic variants lead to severe protein truncation that most likely destabilizes the protein, leading to a loss of function [Kornak et al 2008].


Literature Cited

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Chapter Notes


We thank the families for their continuing participation.

Revision History

  • 12 February 2015 (me) Comprehensive update posted live
  • 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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