3 páginas, 1 figura.Here, we report a family with one child affected by mild DEB. At birth, blistering and denuded areas were present together with the syndactyly of the second and third toes. By the age of 11 mo, blistering was significantly reduced but the blisters healed with hyperpigmented and hypopigmented scars and milia. Both parents and an older sibling were clinically unaffected, and there was no family history of consanguinity or of a blistering disorder or skin fragility.Peer reviewe

Peter B. Cserhalmi-Friedman

Maria C. Garzon

Edwin Guzman

Amalia Martinez-Mir

Wendy K. Chung

Kwame Anyane-Yeboa

Angela M. Christiano

Christiano

Fine

Kivirikko

Journal of Investigative Dermatology

The cycling of carbon on Earth exerts a fundamental influence upon the greenhouse gas content of the atmosphere, and hence global climate over millennia. Until recently, ice sheets were viewed as inert components of this cycle and largely disregarded in global models. Research in the past decade has transformed this view, demonstrating the existence of uniquely adapted microbial communities, high rates of biogeochemical/physical weathering in ice sheets and storage and cycling of organic carbon (>104 Pg C) and nutrients. Here we assess the active role of ice sheets in the global carbon cycle and potential ramifications of enhanced melt and ice discharge in a warming world

Wadham, JL

Hawkings, JR

Tarasov, L

Gregoire, LJ

Spencer, RGM

Gutjahr, M

Ridgwell, A

Kohfeld, KE

White Rose Research Online

Ice sheets matter for the global carbon cycle

Wadham, J. L.

Hawkings, J. R.

Tarasov, L.

Gregoire, L. J.

Spencer, R. G. M.

Gutjahr, Marcus

Ridgwell, A.

Kohfeld, K. E.

OceanRep

Crossref

Maternal Germline Mosaicism in Dominant Dystrophic Epidermolysis Bullosa

The cycling of carbon on Earth exerts a fundamental influence upon the greenhouse gas content of the atmosphere, and hence global climate over millennia. Until recently, ice sheets were viewed as inert components of this cycle and largely disregarded in global models. Research in the past decade has transformed this view, demonstrating the existence of uniquely adapted microbial communities, high rates of biogeochemical/physical weathering in ice sheets and storage and cycling of organic carbon (&gt;104 Pg C) and nutrients. Here we assess the active role of ice sheets in the global carbon cycle and potential ramifications of enhanced melt and ice discharge in a warming world.</p

Spencer, R. G.M.

Gutjahr, M.

Explore Bristol Research

The cycling of carbon on Earth exerts a fundamental influence upon the greenhouse gas content of the atmosphere, and hence global climate over millennia. Until recently, ice sheets were viewed as inert components of this cycle and largely disregarded in global models. Research in the past decade has transformed this view, demonstrating the existence of uniquely adapted microbial communities, high rates of biogeochemical/physical weathering in ice sheets and storage and cycling of organic carbon (&gt;104 Pg C) and nutrients. Here we assess the active role of ice sheets in the global carbon cycle and potential ramifications of enhanced melt and ice discharge in a warming world

eScholarship - University of California

Cserhalmi-Friedman, Peter B.

Garzon, Maria C.

Guzman, Edwin

Martinez-Mir, Amalia

Chung, Wendy K.

Anyane-Yeboa, Kwame

Christiano, Angela M.

Elsevier - Publisher Connector 

REFERENCES
Barnes KC: Evidence for common genetic elements in allergic disease. J Allergy Clin
Immunol 106:192±200, 2000
Becker KG: Comparative genetics of type 1 diabetes and autoimmune disease:
common loci, common pathways? Diabetes 48:1353±1358, 1999
Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison WE, McFarland
HF, Trent JM: Clustering of non-major histocompatibility complex
susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad
Sci USA 95:9979±9984, 1998
Bergmann RL, Bergmann KE, Wahn U: Can we predict atopic disease using
perinatal risk factors? Clin Exp Allergy 28:905±907, 1998
Cornelis F, Faure S, Martinez M et al. New susceptibility locus for rheumatoid
arthritis suggested by a genome-wide linkage study. Proc Natl Acad Sci USA
95:10746±10750, 1998
Dizier MH, Besse-Schmittler C, Guilloud-Bataille M, et al: Genome screen for
asthma and related phenotypes in the french EGEA study. Am J Respir Crit Care
Med 162:1812±1818, 2000
Encinas JA, Wicker LS, Peterson LB, et al: VK QTL in¯uencing autoimmune
diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nat
Genet 21:158±160, 1999
Green®eld EA, Nguyen KA, Kuchroo VK: CD28/B7 costimulation. a review. Crit
Rev Immunol 18:389±418, 1998
Lee YA, Wahn U, Kehrt R, et al: major susceptibility locus for atopic dermatitis maps
to chromosome 3q21. Nat Genet 26:470±473, 2000
Mein CA, Esposito L, Dunn MG, et al: A search for type 1 diabetes susceptibility
genes in families from the United Kingdom. Nat Genet 19:297±300, 1998
Morel L, Blenman KR, Croker BP, Wakeland EK: The major murine systemic lupus
erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes
Proceedings Natl Acad Sci USA 98:1787±1792, 2001
Myerscough A, John S, Barrett JH, Ollier WE, Worthington J: Linkage of
rheumatoid arthritis to insulin-dependent diabetes mellitus loci: evidence
supporting a hypothesis for the existence of common autoimmune
susceptibility loci. Arthritis Rheum 43:2771±2775, 2000
Teuscher C, Hickey WF, Grafer CM, Tung KS: A common immunoregulatory
locus controls susceptibility to actively induced experimental allergic
encephalomyelitis and experimental allergic orchitis in BALB/c mice. J
Immunol 160:2751±2756, 1998
Vyse TJ, Todd JA: Genetic analysis of autoimmune disease. Cell 85:311±318, 1996
Maternal Germline Mosaicism in Dominant Dystrophic
Epidermolysis Bullosa
To the Editor:
The dystrophic form of epidermolysis bullosa (DEB) can be
inherited in both an autosomal dominant or a recessive fashion
(Christiano and Uitto, 1996). The recessive form can range from a
very severe condition (Hallopeau-Siemens DEB) to a relatively
mild disease, clinically indistinguishable from the dominantly
inherited mild form of DEB, (DDEB) (Fine et al, 2000). A new
case of mild DEB, therefore, always presents the problem of
differentiating recessively inherited vs. dominantly inherited DEB
due either to de novo mutations or to germline mosaicism. The
latter was previously suggested in the junctional form of
epidermolysis bullosa, which originates from mutations in the
genes encoding laminin 5 (Kivirikko et al, 1996), but has not been
demonstrated in the case of DEB.
Here, we report a family with one child affected by mild DEB.
At birth, blistering and denuded areas were present together with
the syndactyly of the second and third toes. By the age of 11 mo,
blistering was signi®cantly reduced but the blisters healed with
hyperpigmented and hypopigmented scars and milia. Both parents
and an older sibling were clinically unaffected, and there was no
family history of consanguinity or of a blistering disorder or skin
fragility.
Screening for mutations in the COL7A1 gene in the patient
using previously described techniques (Christiano et al, 1997)
revealed a single glycine substitution in the triple helical domain of
the type VII collagen gene (G2003R), which has previously been
associated with Bart's syndrome, a form of DDEB (Christiano et al,
1996). This mutation, however, was not found in the peripheral
blood DNA of the clinically unaffected parents and the sibling
(Fig 1). As nonpaternity based on parental interviews was unlikely,
we concluded that the mutation was most likely a de novo event in
the patient, and would be associated with little risk of recurrence.
Nevertheless, the parents were appropriately counselled that the
possibility of having another affected child existed, if the mutation
existed as a germline mosaic transmitted from either parent ± a
possibility that was considered remote.
Shortly after completing the mutation analysis, the mother
became pregnant and the parents requested prenatal diagnosis.
DNA isolated from the amniotic ¯uid sample was used as template
for polymerase chain reaction ampli®cation and automated
sequencing. Unexpectedly, the mutation G2003R was also present
in the fetus, suggesting that the initial occurrence was in fact not a
de novo event. We could only explain the second occurrence of the
Manuscript received January 30, 2001; revised March 20, 2001; accepted
for publication March 26, 2001.
Reprint requests to: Dr. Angela M. Christiano, Department of
Dermatology, College of Physicians & Surgeons, Columbia University,
630 West 168th Street VC-1526, New York, NY 10032. Email:
amc65@columbia.edu
Figure 1. Haplotype analysis of a pedigree with DEB. The ®gure
shows the haplotype of the family members, listed according to the
microsatellite markers indicated on the left. The mutation G2003R is
also listed. The ®gure demonstrates that all three offspring (individuals II-
1 to II-3) carry the same maternal (individual I-2) chromosome 3
haplotype. The two affected individuals (individuals II-2 and II-3) display
different paternal chromosome 3 haplotype. The mutation G2003 is
present only in individuals II-2 and II-3 (gray shading), suggesting that it
is only contained in a percentage of the maternal chromosomes.
VOL. 117, NO. 5 NOVEMBER 2001 LETTERS TO THE EDITOR 1327
identical mutation in this family by invoking the possibility of
germline mosaicism. To further investigate the parental transmis-
sion of the mutation, we performed haplotype analysis using
chromosome 3 microsatellite markers (Fig 1), synthesized based on
publicly available oligonucleotide sequences (Cooperative Human
Linkage Center and Genome Database). Polymerase chain reaction
products containing microsatellite markers for chromosome 3 were
analyzed on a 6% nondenaturing polyacrylamide gel. We deter-
mined that all three offspring carried the same maternal chromo-
some 3 haplotype. The clinically unaffected sister of the patient and
the affected fetus shared the same paternal chromosome; however,
the patient carried the other paternal chromosome. Thus, we
concluded that the mutation is most likely present in a percentage
of cells in the germline of the mother.
To our knowledge, this study represents the ®rst documented
case of germline mosaicism in epidermolysis bullosa and serves as a
reminder that germline mosaicism should be considered in every
case when a mutation is found in the offspring but not in the
parents. In the event of a de novo mutation, the family can be
counselled that the likelihood of having another affected child is the
same as in the general population. In the case of germline
mosaicism, however, the likelihood of having another affected
child is much higher, depending on the ratio of mutant to wild-
type germ cells. This possibility has a signi®cant impact on genetic
counselling, and unfortunately, exact determination of the trans-
mitting parent is not always possible. In the case of paternal
transmission, a semen sample can be used for further studies to
determine the percentage of mutant germ cells, and thus calculate
an accurate risk of recurrence for the family. These ®ndings
heighten our awareness of the existence of unusual modes of
inheritance in epidermolysis bullosa, which should be taken into
account when counselling families about the recurrence risk for
future offspring.
Peter B. Cserhalmi-Friedman,* Maria C. Garzon,*
Edwin Guzman,³ Amalia Martinez-Mir,* Wendy K. Chung,³
Kwame Anyane-Yeboa,³ and Angela M. Christiano*²
*Departments of Dermatology, ²Genetics and Development and
³Pediatrics, Division of Clinical Genetics, College of Physicians
and Surgeons, Columbia University, New York, New York,
U.S.A.
REFERENCES
Christiano AM, Bart BJ, Epstein EH Jr, Uitto J: Genetic basis of Bart's syndrome: a
glycine substitution mutation in the type VII collagen gene. J Invest Dermatol
106:1340±1342, 1996
Christiano AM, Hoffman GG, Zhang X, Xu Y, Tamai Y, Greenspan DS, Uitto J:
Strategy for identi®cation of sequence variants in COL7A1 and a novel 2-bp
deletion mutation in recessive dystrophic epidermolysis bullosa. Hum Mutat
10:408±414, 1997
Christiano AM, Uitto J: Molecular complexity of the cutaneous basement membrane
zone. Revelations from the paradigms of epidermolysis bullosa. Exp Dermatol
5:1±11, 1996
Fine JD, Eady RA, Bauer EA, et al: Revised classi®cation system for inherited
epidermolysis bullosa: Report of the second international consensus meeting on
diagnosis and classi®cation of epidermolysis bullosa. J Am Acad Dermatol
42:1051±1066, 2000
Kivirikko S, McGrath JA, Pulkkinen L, Uitto J, Christiano AM: Mutational hotspots
in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis
bullosa. Hum Mol Genet 5:231±237, 1996
1328 LETTERS TO THE EDITOR THE JOURNAL OF INVESTIGATIVE DERMATOLOGY


Maternal Germline Mosaicism in Dominant Dystrophic Epidermolysis Bullosa 

Cserhalmi-Friedman, P. B.

Garzón, María C.

Martínez Mir, Amalia

Digital.CSIC

Maternal Germline Mosaicism in Dominant Dystrophic Epidermolysis Bullosa Peter B Cserhalmi-Friedman*, Maria C Garzon*, Edwin Guzman‡, Amalia Martinez-Mir*, Wendy K Chung‡, Kwame Anyane-Yeboa‡ and Angela M Christiano*,† *Department of Dermatology, New York, New York, U.S.A. †Department of Genetics and Development, New York, New York, U.S.A. ‡Department of Pediatrics, Division of Clinical Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. Correspondence: Dr Angela M. Christiano, Department of Dermatology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street VC-1526, New York, NY 10032 Email:amc65@columbia.edu To the Editor: The dystrophic form of epidermolysis bullosa (DEB) can be inherited in both an autosomal dominant or a recessive fashion (Christiano and Uitto, 1996). The recessive form can range from a very severe condition (Hallopeau-Siemens DEB) to a relatively mild disease, clinically indistinguishable from the dominantly inherited mild form of DEB, (DDEB) (Fine et al, 2000). A new case of mild DEB, therefore, always presents the problem of differentiating recessively inherited vs. dominantly inherited DEB due either to de novo mutations or to germline mosaicism. The latter was previously suggested in the junctional form of epidermolysis bullosa, which originates from mutations in the genes encoding laminin 5 (Kivirikko et al, 1996), but has not been demonstrated in the case of DEB. Here, we report a family with one child affected by mild DEB. At birth, blistering and denuded areas were present together with the syndactyly of the second and third toes. By the age of 11 mo, blistering was significantly reduced but the blisters healed with hyperpigmented and hypopigmented scars and milia. Both parents and an older sibling were clinically unaffected, and there was no family history of consanguinity or of a blistering disorder or skin fragility. Screening for mutations in the COL7A1 gene in the patient using previously described techniques (Christiano et al, 1997) revealed a single glycine substitution in the triple helical domain of the type VII collagen gene (G2003R), which has previously been associated with Bart's syndrome, a form of DDEB (Christiano et al, 1996). This mutation, however, was not found in the peripheral blood DNA of the clinically unaffected parents and the sibling Figure 1. As nonpaternity based on parental interviews was unlikely, we concluded that the mutation was most likely a de novo event in the patient, and would be associated with little risk of recurrence. Nevertheless, the parents were appropriately counselled that the possibility of having another affected child existed, if the mutation existed as a germline mosaic transmitted from either parent – a possibility that was considered remote. Shortly after completing the mutation analysis, the mother became pregnant and the parents requested prenatal diagnosis. DNA isolated from the amniotic fluid sample was used as template for polymerase chain reaction amplification and automated sequencing. Unexpectedly, the mutation G2003R was also present in the fetus, suggesting that the initial occurrence was in fact not a de novo event. We could only explain the second occurrence of the identical mutation in this family by invoking the possibility of germline mosaicism. To further investigate the parental transmission of the mutation, we performed haplotype analysis using chromosome 3 microsatellite markers Figure 1, synthesized based on publicly available oligonucleotide sequences (Cooperative Human Linkage Center and Genome Database). Polymerase chain reaction products containing microsatellite markers for chromosome 3 were analyzed on a 6% nondenaturing polyacrylamide gel. We determined that all three offspring carried the same maternal chromosome 3 haplotype. The clinically unaffected sister of the patient and the affected fetus shared the same paternal chromosome; however, the patient carried the other paternal chromosome. Thus, we concluded that the mutation is most likely present in a percentage of cells in the germline of the mother. To our knowledge, this study represents the first documented case of germline mosaicism in epidermolysis bullosa and serves as a reminder that germline mosaicism should be considered in every case when a mutation is found in the offspring but not in the parents. In the event of a de novo mutation, the family can be counselled that the likelihood of having another affected child is the same as in the general population. In the case of germline mosaicism, however, the likelihood of having another affected child is much higher, depending on the ratio of mutant to wild-type germ cells. This possibility has a significant impact on genetic counselling, and unfortunately, exact determination of the transmitting parent is not always possible. In the case of paternal transmission, a semen sample can be used for further studies to determine the percentage of mutant germ cells, and thus calculate an accurate risk of recurrence for the family. These findings heighten our awareness of the existence of unusual modes of inheritance in epidermolysis bullosa, which should be taken into account when counselling families about the recurrence risk for future offspring. References 1. Christiano, AM, Bart, BJ, Epstein, EH, Jr, Uitto, J:Genetic basis of Bart's syndrome: a glycine substitution mutation in the type VII collagen gene. J Invest Dermatol 1996, 106: 1340–1342 2. Christiano, AM, Hoffman, GG, Zhang, X, Xu, Y, Tamai, Y, Greenspan, DS, Uitto, J:Strategy for identification of sequence variants in COL7A1 and a novel 2-bp deletion mutation in recessive dystrophic epidermolysis bullosa.Hum Mutat 1997, 10: 408–414 3. Christiano, AM & Uitto, J:Molecular complexity of the cutaneous basement membrane zone. Revelations from the paradigms of epidermolysis bullosa.Exp Dermatol 1996, 5: 1–11 4. Fine, JD, Eady, RA, Bauer, EA, et al: Revised classification system for inherited epidermolysis bullosa: Report of the second international consensus meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 2000, 42: 1051–1066 5. Kivirikko, S, McGrath, JA, Pulkkinen, L, Uitto, J, Christiano, AM:Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa. Hum Mol Genet 5: 231–237, 1996 Figures  Haplotype analysis of a pedigree with DEB. The figure shows the haplotype of the family members, listed according to the microsatellite markers indicated on the left. The mutation G2003$ is also listed. The figure demonstrates that all three offspring (individuals II-1 to II-3) carry the same maternal (individual I-2) chromosome 3 haplotype. The two affected individuals (individuals II-2 and II-3) display different paternal chromosome 3 haplotype. The mutation G2003 is present only in individuals II-2 and II-3 (gray shading), suggesting that it is only contained in a percentage of the maternal chromosomes. 

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Maternal Germline Mosaicism in Dominant Dystrophic Epidermolysis Bullosa

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