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FBLN5-Related Cutis Laxa

Synonyms: Autosomal Recessive Cutis Laxa, Pulmonary Emphysema Type; Autosomal Recessive Cutis Laxa Type 1

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Centre de génétique humaine
CHU
Université de Franche-Comté
Besançon, France
, MD, PhD
Center for Medical Genetics
Antwerp University Hospital
Edegem, Belgium

Initial Posting: ; Last Update: March 13, 2014.

Summary

Disease characteristics. FBLN5-related cutis laxa 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.

Diagnosis/testing. Diagnosis is based on clinical findings and electron microscopic (EM) findings on skin biopsy. FBLN5 is the only gene in which pathogenic variants cause this disorder.

Management. Treatment of manifestations: Routine repair of inguinal hernias; repeat plastic surgery of the face and trunk as needed; symptomatic treatment of pulmonary emphysema. No treatment is available for the arterial abnormalities.

Prevention of secondary complications: Attention to respiratory function prior to surgery; prophylactic antibiotics as needed for vesicoureteral reflux.

Agents/circumstances to avoid: Smoking.

Genetic counseling. FBLN5-related cutis laxa can be inherited in an autosomal recessive or autosomal dominant manner. Autosomal recessive inheritance is more common.

  • Autosomal recessive inheritance: 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.
  • Autosomal dominant inheritance: Each child of an individual with autosomal dominant cutis laxa has a 50% chance of inheriting the pathogenic variant.

Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant(s) have been identified.

Diagnosis

Clinical Diagnosis

FBLN5-related cutis laxa is diagnosed in individuals with the following:

  • Cutis laxa. Furrowing of the skin of the whole body that is particularly obvious in neck, axillae, and groin. The face has a “droopy” appearance with eyelid ptosis and drooping cheeks. When one tries to extend the skin, it does not display hyperelasticity as in the Ehlers-Danlos syndromes, but rather keeps its consistency.
  • Pulmonary emphysema. Pulmonary emphysema is usually seen at an early age, including the neonatal period.
  • Arterial involvement. Peripheral pulmonary artery stenosis appears to be specific for this disorder. Some affected individuals also display supravalvular aortic stenosis.
  • Other evidence of a generalized connective disorder
    • Inguinal hernias
    • Hollow viscus diverticula (e.g., intestine, bladder)
    • Pyloric stenosis

Testing

Skin biopsy with orcein staining on paraffin-embedded samples

  • Light microscopy. Normal or mild fragmentation and paucity/absence of elastic fibers
  • Electron microscopy (EM). Paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [Ledoux-Corbusier 1983]. These findings are in contrast to those of Debré-type cutis laxa (see ATP6V0A2-Related Cutis Laxa) and De Barsy syndrome (see Differential Diagnosis), in which a sparse elastic network, but not defective assembly of ELN fibers, is observed. Because deficiency of other proteins or cofactors involved in the process of elastic fiber assembly could potentially give the same ultrastructural picture, it is not known whether this feature is specific for FBLN5-related cutis laxa.

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

Molecular Genetic Testing

Genes. FBLN5 (known previously as EVEC or DANCE) is the only gene in which pathogenic variants are known to cause FBLN5-related cutis laxa.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in FBLN5-Related Cutis Laxa

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
FBLN5Sequence analysis 2<100%
Deletion/duplication analysis 3See footnote 4

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

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

3. Testing that identifies exonic 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.

4. Duplication reported in one case of autosomal dominant disease [Markova et al 2003]; see Table 3. No exonic or whole-gene deletions or duplications are known to cause the autosomal recessive form of the disease.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • The diagnosis of FBLN5-related cutis laxa is established in individuals who meet clinical diagnostic criteria and have pathogenic variants identified in FBLN5.
  • Molecular genetic testing begins with sequence analysis.
  • If a pathogenic variant is not identified (or in the case of autosomal recessive FBLN5-related cutis laxa, if no or only one pathogenic variant is identified), deletion/duplication analysis is considered.

Molecular genetic testing

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having FBLN5-related cutis laxa is sequence analysis of the gene.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having FBLN5-related cutis laxa is use of a multi-gene panel. See Differential Diagnosis.

Clinical Description

Natural History

In addition to cutis laxa (the most common finding in FBLN5-related cutis laxa), most affected individuals have early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder including inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvular aortic stenosis is observed. Intrafamilial variability in age of onset is observed.

Infections secondary to vesicoureteral reflux (e.g., pyelonephritis) are observed. In one individual, the bladder was described on voiding cystouretrogram as having an unusual “cauliflower” shape secondary to the presence of multiple diverticula; a similar bladder appearance has been observed in individuals with Menkes disease.

Pulmonary artery stenosis, congenital heart disease, and/or hollow viscus diverticula are likely to cause early death. Peripheral pulmonary artery stenoses lead to ventricular dilatation and contribute to progressive heart failure. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death. For those who survive early childhood, pulmonary emphysema, cor pulmonale, and multiple surgeries are the rule. Prolonged survival is exceptional; the oldest known person with this disorder was a high-functioning young woman who died at age 21 years from cor pulmonale.

Hip dislocation is not observed in FBLN5-related cutis laxa.

Intelligence is normal [Van Maldergem et al 1988].

Autosomal recessive FBLN5-related cutis laxa. To date, five families with autosomal recessive FBLN5-related cutis laxa have been described [Van Maldergem et al 1988, Karakurt et al 2001, Loeys et al 2002, Pour-Jafari & Sahiri 2004, Claus et al 2008, Callewaert et al 2013]. A listing of cases reported in the literature and fulfilling clinical criteria for FBLN5-related cutis laxa can be found in Appendix 1 of Van Maldergem et al [2008].

In the first family described, all six affected individuals had severe congenital cutis laxa and all but one had severe, variable pulmonary emphysema; the sixth was said to have normal chest x-rays. Ages of death ranged from six months to 21 years. Of note, the initial description of this family was expanded to include two relatives living in Western Europe and then a relative living in Turkey, who had initially been described as having Debré-type cutis laxa [Karakurt et al 2001]. The disorder in the latter individual was reclassified clinically as “pulmonary emphysema-type cutis laxa” based on his facial appearance in published photographs and then molecularly confirmed with identification of homozygosity for the same FBLN5 base pair change (T998C) observed in the remainder of the family. Subsequent genealogic studies identified a common ancestor.

In the second family, two affected children from an apparently unrelated family from Iran shared a similar clinical presentation plus supravalvular aortic stenosis. The children died at ages two years and 14 years. No common ancestor was found with the first family reported; however, homozygosity for the same base pair change (T998C) in these two children suggested identity by descent, which was supported by haplotype studies using polymorphic markers [Elahi et al 2006].

In a third family in which two children had cutis laxa, emphysema, and inguinal hernias, both children were alive at ages five and eight years [Claus et al 2008].

Two additional families, one from Algeria and the other from Lebanon, each with three affected individuals, presented with similar phenotypes [Callewaert et al 2013]. In the Algerian family, a homozygous c.1171G>T (p.Glu391Ter) nonsense mutation was observed, affecting the FBLN-specific domain, while in the Lebanese family, a c.649T>C homozygous missense mutation, resulting in p.Cys217Arg residue change in the fourth cbEGF-like domain of the protein was observed. In the Lebanese family, all three affected siblings underwent surgery in the first months of life for pyloric stenosis; aortic valve dysplasia (stenosis and regurgitation) was reported in one affected child.

Heterozygous carriers for autosomal recessive FBLN5-related cutis laxa. To date, no evidence has shown that heterozygous carriers in these families develop AMD.

Autosomal dominant FBLN5-related cutis laxa. Based on the description of the only family reported to date to have demonstrated autosomal dominant inheritance, this form appears to be milder in clinical presentation with less internal organ involvement than the autosomal recessive form [Markova et al 2003].

Genotype-Phenotype Correlations

Mutation of FBLN5 can cause either autosomal recessive or autosomal dominant cutis laxa resulting from alterations of the microfibrillar component of elastic fibers:

  • Recessive pathogenic variants entail loss of function resulting from aberrant folding and intracellular retention [Loeys et al 2002].
  • An affected individual from the only reported family with autosomal dominant inheritance had an elongated, stable protein that acted in a dominant-negative manner [Markova et al 2003].
  • One other individual who was heterozygous for an inherited FBLN5 allele (p.Gly202Arg) and compound heterozygous for ELN alleles has been reported. It was hypothesized that the FBLN5 allele modified the phenotype caused by the ELN pathogenic variants in the context of inflammatory destruction of elastic fibers in an acquired form of cutis laxa [Hu et al 2006].

Prevalence

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

Differential Diagnosis

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

FBLN4 (EFEMP2)-related cutis laxa (ARCL1). EFEMP2-related cutis laxa (autosomal recessive cutis laxa type 1A [ARCL1A]) 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. The cutis laxa and emphysema are similar in FBLN4- or FBLN5-related cutis laxa; however, to date, the diaphragmatic changes and arterial aneurysms seem more predominant in FBLN4 (EFEMP2)-related cutis laxa.

ATP6V0A2-related cutis laxa (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, but not all, affected individuals, cortical and cerebellar malformations are present and are associated with severe developmental delays, seizures, and neurologic regression. Clinical features that distinguish FBLN5-related cutis laxa from ARCL2A are absence of intellectual disability, hip dislocation, and delayed closure of the fontanelle. In individuals with ARCL2A, EM findings of skin biopsy, rarefaction of ELN fibers composed of ELN and elastofibrils, and abnormal serum transferrin isoelectrofocusing (IEF) may help confirm the diagnosis.

ELN-related cutis laxa (ADCL) 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 (so-called cystic media degeneration) 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].

Gerodermia osteodysplastica (GO). Onset occurs in infancy or early childhood [Nanda et al 2008]. Children appear older than their age as a result 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. 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. Mutation of SCYL1BP1 is causative [Hennies et al 2008].

De Barsy syndrome 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, pseudoathetoid movements, and hyperreflexia are observed. Inheritance is autosomal recessive; with the exception of PYCR1 (in which mutation accounts for a small percentage of De Barsy syndrome), the gene(s) associated with this disorder are not known.

LTBP4-related cutis laxa, first reported as a single case, is characterized by a cutaneous phenotype similar to that of FBLN5-related cutis laxa and by severe multiple malformations including congenital heart disease, pulmonary arterial stenosis and, interestingly, pulmonary hypertension. The latter appears to be a distinctive feature as it was observed in two patients in the authors’ series. Bladder diverticulae, noticeably absent in the other entities discussed in this section, have also been described.

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

Disease NameGene OMIM #MOIClinical Findings
Cutis Laxa EmphysemaAneurysmsIntellectual DisabilityGI and GU Malformations
ARCL1AFBLN5219100
604580
AR++++++--+
ARCL1B EFEMP2614437
604633
AR +++++++--
ARCL1C (URDS)LTBP4613177
604710
AR+++++--+++
ARCL2AATP6V0A2278250
219200
AR++--++-
ARCL2BPYCR1612940
614438
179035
AR+++-++-
ADCLELN or FBLN5123700
130160
604580
AD+++--
GOSCYL1BP1231070AR+ +----
De Barsy syndromePYCR1 1219150AR+--+++-

MOI = mode of inheritance

1. Pathogenic variants in PYCR1 account for a small percentage of De Barsy syndrome.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FBLN5-related cutis laxa, the following evaluations are recommended:

  • Chest roentgenogram
  • Echocardiogram
  • Kidney ultrasound examination
  • Medical genetics consultation

If clinically indicated:

  • Pulmonary vessel angiogram
  • Barium enema
  • Voiding cystouretrogram (VCUG)

Treatment of Manifestations

Appropriate treatment for:

  • Inguinal hernias. Routine repair
  • Cutis laxa. Repeat plastic surgery of the face and trunk as needed
  • Pulmonary emphysema. Symptomatic treatment
  • Arterial abnormalities. No treatment available

Prevention of Secondary Complications

The following are appropriate:

  • Attention to respiratory function prior to surgery
  • Prophylactic antibiotics (cotrimoxazole) in case of vesicoureteral reflux

Surveillance

Routine surveillance of the urinary tract for evidence of bladder diverticula and/or vesicoureteral reflux is indicated.

Agents/Circumstances to Avoid

Smoking is contraindicated; however, the limited life span of affected individuals makes this recommendation mostly theoretic.

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

FBLN5-related cutis laxa can be inherited in an autosomal recessive or autosomal dominant manner. Autosomal recessive inheritance is more common.

Risk to Family Members – Autosomal Recessive Inheritance

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. Individuals with autosomal recessive FBLN5-related cutis laxa have not been reported to reproduce. If they were to reproduce, their offspring would be obligate heterozygotes (carriers) for a pathogenic variant.

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 of at-risk relatives is possible if the pathogenic FBLN5 variants have been identified in the family.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Rare individuals diagnosed with autosomal dominant FBLN5-related cutis laxa have an affected parent.
  • A proband with autosomal dominant FBLN5-related cutis laxa may have the disorder as the result of de novo mutation. The proportion of cases caused by de novo mutation is unknown
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include a dermatologic examination and molecular genetic testing for the pathogenic variant identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.

Offspring of a proband. Each child of an individual with autosomal dominant cutis laxa has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

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

Prenatal Testing

If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant(s) 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.

  • DermNet NZ
    New Zealand
  • Medline Plus
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    1 AMS Circle
    Bethesda MD 20892-3675
    Phone: 877-226-4267 (toll-free); 301-565-2966 (TTY)
    Fax: 301-718-6366
    Email: niamsinfo@mail.nih.gov

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. FBLN5-Related Cutis Laxa: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FBLN514q32​.12Fibulin-5FBLN5 homepage - Mendelian genesFBLN5

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 FBLN5-Related Cutis Laxa (View All in OMIM)

219100CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IA; ARCL1A
604580FIBULIN 5; FBLN5
614434CUTIS LAXA, AUTOSOMAL DOMINANT 2; ADCL2

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 then further processed [Kielty 2006]. Enzymes necessary for the conversion of tropoelastin into ELN are the lysyl oxidases, a group of copper-dependent enzymes (deficient in secondary cutis laxa associated with treatment with copper chelators like penicillamine) which form covalent crosslinks between ELN molecules. Elastic fibers not only increase the elasticity of the extracellular matrix, but also influence its architecture and regulate TGFβ-signaling.

When tropoelastin expression is insufficient, the generation of elastic fibers is disturbed. This explains why heterozygous loss-of-function ELN pathogenic variants cause alterations that primarily affect the vasculature (supravalvular aortic stenosis) and only minimally affect the skin. In autosomal dominant cutis laxa, ELN pathogenic variants are mostly confined to the 3’ end of the gene [Metcalfe et al 2000]. These variants result in secretion of abnormal tropoelastin molecules that interfere with elastic fiber assembly in a dominant-negative fashion [Zhang et al 1999].

Pathogenic variants in FBLN5 can cause either dominant or recessive cutis laxa resulting from alterations of the microfibrillar component of the elastic fibers. The dominant pathogenic variants lead to an elongation of the protein that is stable and can act in a dominant-negative manner [Markova et al 2003], whereas the recessive pathogenic variants entail loss of function as a result of aberrant folding and intracellular retention [Loeys et al 2002, Hu et al 2006]. The same applies to recessive pathogenic variants in FBLN4 (EFEMP2) [Hucthagowder et al 2006] (see EFEMP2-Related Cutis Laxa).

A more complex mechanism underlies autosomal recessive cutis laxa, Debré type (ARCL2A) (see ATP6V0A2-Related Cutis Laxa). Here, the 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 two lines of evidence suggest that a defect of the secretory pathway is the basis of the elastic fiber defect in ARCL2A:

  • Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [Morava et al 2005, Kornak et al 2008, Van Maldergem et al 2008].
  • Patient cells 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. FBLN5 consists of 13 exons that are differentially combined in three major transcripts. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. See Table 3. The only annotated nonsynonymous coding normal variant in FBLN5 resides in exon 10 and leads to a p.Asp364Tyr change.

Pathogenic allelic variants. See Table 3.

  • Autosomal recessive FBLN5-related cutis laxa: p.Cys217Arg (in 2 families), p.Ser227Pro (in 2 likely related families), p.Gly202Arg, and p.Glu391Ter [Loeys, personal communication]
  • Autosomal dominant FBLN5-related cutis laxa: a 22,729-bp duplication comprising all of exons 5 to 8 and the first 9 bp of exon 9 [Markova et al 2003]

Table 3. FBLN5 Variants

Class of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid Change Reference Sequences
Benignc.1090G>T 2p.Asp364TyrNM_006329​.3
NP_006320​.2
Pathogenicc.604G>Ap.Gly202Arg
c.649T>Cp.Cys217Arg
c.679T>C
(T998C)
p.Ser227Pro
c.1171G>Tp.Glu391Ter
(380-9063_872dup22729) 3See footnote 4

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.

1. Variant designation that does not conform to current naming conventions

2. rs1802492

3. Duplication of 22,729 nucleotides from intron 4 to exon 9 [Markova et al 2003]

4. Duplication results in a tandem duplication of 483 nucleotides in the transcript resulting in tandem duplication of four cbEGF motifs in the protein product [Markova et al 2003]. The only pathogenic variant known to cause the autosomal dominant form of the disease.

Normal gene product. Fibulin-5, the protein encoded by FBLN5, is an extracellular matrix protein involved in the formation of the microfibrillar scaffold of the elastic fibers. It contains calcium-binding EGF-like repeats and an RGD-motif and is approximately 55 kd in size. The same applies to fibulin-4, encoded by FBLN4 (EFEMP2), except that fibulin-4 does not contain an RGD-motif.

Abnormal gene product. Autosomal recessive variants in FBLN5 result in intracellular retention of the misfolded protein [Hu et al 2006], resulting in a loss of function. Autosomal dominant variants lead to an elongation of the protein that is stable and can act in a dominant-negative manner [Markova et al 2003].

References

Literature Cited

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Chapter Notes

Acknowledgments

We thank the families for their participation.

Revision History

  • 13 March 2014 (me) Comprehensive update posted live
  • 13 October 2011 (me) Comprehensive update posted live
  • 19 March 2009 (et) Review posted live
  • 10 September 2008 (lvm) Original submission
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