Enamel Defects in Carriers of a Novel LAMA3 Mutation Underlying Epidermolysis Bullosa

Yuen, Wing Yan; Pasmooij, Anna M. G.; Stellingsma, Cornelis; Jonkman, Marcel F.

doi:10.2340/00015555-1341

Cited by 37 publications

(44 citation statements)

References 8 publications

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“…The father displayed subtle enamel pitting of secondary dentition ( Figure 1b) and had no history of skin blistering. The mother (II-6) carried the missense mutation c.(4484C4T); p.(Ala1495Val) in exon 33, a mutation earlier reported in Yuen et al 5 Dental screening for pathology was negative in the mother, and dermatological examination was unremarkable. The parents reported that the index patient's two older brothers (III-1 and III-2) had no skin disease or dental problems, but were unavailable for objective examination and mutation analysis.…”

Section: Resultsmentioning

confidence: 75%

“…2,5,[10][11][12][13][14] In the examined heterozygous null carriers in both our families, dental pathology was localized focally, clinically asymptomatic and therefore not brought to attention until we examined JEB in their offspring. Since the first report of enamel abnormalities in LAMA3 null mutation carriers by Yuen et al, 5 we began to screen carriers of LAMA3 mutations for dental pitting. The low incidence of LAMA3 mutations, subtle nature of changes and lack of direct screening may explain the scarcity of reports of enamel defects in this population.…”

Section: Discussionmentioning

confidence: 98%

“…4 The mechanism by which the heterozygous functional null mutations in LAMA3 result in disease appears to be haploinsufficiency, as we suggested before. 5 In skin, keratinocyte adhesion is redundantly regulated, and if LM-332 is half dose, it is most likely sufficiently compensated for by other epidermal proteins, such as integrins. 5,15 The splice-site mutation c.4684+1G4A behaves like a LAMA3 null mutation, as o2% expression of intact laminin α3 protein was detected in the immunoblot (Figure 2d).…”

Section: Discussionmentioning

confidence: 99%

“…5 In skin, keratinocyte adhesion is redundantly regulated, and if LM-332 is half dose, it is most likely sufficiently compensated for by other epidermal proteins, such as integrins. 5,15 The splice-site mutation c.4684+1G4A behaves like a LAMA3 null mutation, as o2% expression of intact laminin α3 protein was detected in the immunoblot (Figure 2d). The low amount of polypeptide can be explained by the detrimental effect on protein stability of the deleted amino acids in the G5 subdomain (codons 1509-1606) encoded by exons 34 and 35.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Recently, we reported that heterozygous carriers of loss of function (null) mutations in LAMA3 exhibit dental abnormalities without skin symptoms. 5 Carriers exhibited localized enamel pitting and hypoplasia of secondary dentition. Here, we report two new heterozygous carriers affected with dental abnormalities from loss of function mutations in LAMA3.…”

Section: Introductionmentioning

confidence: 99%

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Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Gostyńska¹,

Yuen²,

Pasmooij³

et al. 2016

Eur J Hum Genet

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The hereditary blistering disease junctional epidermolysis bullosa (JEB) is always accompanied by structural enamel abnormalities of primary and secondary dentition, characterized as amelogenesis imperfecta. Autosomal recessive mutations in LAMA3, LAMB3 and LAMC2 encoding the heterotrimer laminin 332 (LM-332) are among the genes causing JEB. While examining pedigrees of JEB patients with LAMA3 mutations, we observed that heterozygous carriers of functional null mutations displayed subtle enamel pitting in the absence of skin fragility or other JEB symptoms. Here, we report two new LAMA3 functional null mutations: nonsense c.2377C4T p.(Arg793Ter) and splice-site c.4684+1G4A mutation in heterozygous carriers exhibiting enamel pitting. Both parents had offspring affected with JEB and displayed subtle enamel pitting of secondary dentition without any sign of skin blistering. The reported enamel abnormality in LAMA3 mutation carriers could be attributed to a half dose effect of the laminin α3 chain (haploinsufficiency).

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Gostyńska¹,

Yuen²,

Pasmooij³

et al. 2016

Eur J Hum Genet

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ENAM mutations and digenic inheritance

Zhang

Seymen

et al. 2019

Molec Gen & Gen Med

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Background ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when both ENAM alleles are defective.MethodsWhole exome sequences of recruited AI probands were initially screened for mutations in known AI candidate genes. Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co‐occurrence of ENAM and LAMA3 mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam+/+Ambn +/+, Enam+/−, Ambn+/−, and Enam+/−Ambn+/− mice was characterized by dissection and backscattered scanning electron microscopy (bSEM).Results ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single‐nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133‐1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single‐nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921‐1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single‐nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous LAMA3 mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation. In mice, Ambn+/− maxillary incisors were normal. Ambn+/− molars were also normal, except for minor surface roughness. Ambn+/− mandibular incisors were sometimes chalky and showed minor chipping. Enam+/− incisor enamel was thinner than normal with ectopic mineral deposited laterally. Enam+/− molars were sometimes chalky and rough surfaced. Enam+/−Ambn+/− enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition.ConclusionNovel ENAM mutations causing AI were identified, raising to 22 the number of ENAM variations known to cause AI. The severity of the enamel phenotype in Enam+/−Ambn+/− double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.

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Junctional Epidermolysis Bullosa, Generalized Intermediate Type

Jonkman

Mellerio

2015

Blistering Diseases

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Enamel Defects in Carriers of a Novel LAMA3 Mutation Underlying Epidermolysis Bullosa

Cited by 37 publications

References 8 publications

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

ENAM mutations and digenic inheritance

Junctional Epidermolysis Bullosa, Generalized Intermediate Type

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