I. Department of Obstetrics and Gynaecology,
Semmelweis University Medical School,
Budapest, Hungary
To the Editor:
Recently, an interesting observation has been reported by Gebbia
et al1 in this journal regarding
connexin43 gene mutations in patients with heterotaxy.
Previously, another paper was published by Britz-Cunningham et
al2 reporting human connexin43 gene
mutations in patients with visceroatrial heterotaxy syndrome. Their
article was referred to in the McKusick catalogue in the description of
Ivemark syndrome (MIM 208530),3 and
connexin43 mutations were thought to be the cause of
asplenia and polysplenia syndromes with cardiovascular
anomalies. Only some hundred such cases have been reported so far in
the literature, and most of them were sporadic, although familiar
occurrences have also been described, suggesting autosomal recessive
inheritance.3 The first evidence for the
autosomal recessive inheritance was the identification of
connexin43 gene mutations in these patients by
Britz-Cunningham et al.2 Two other groups
examined connexin43 mutations in patients with heterotaxy
syndromes, but neither of them could detect any mutation in the
cytoplasmic carboxy terminal region of the
gene.4 5 Gebbia and
colleagues1 continued the search for mutation in
additional patients with sporadic and familial heterotaxy, but they
could not detect any connexin43 mutation in any patients
with heterotaxy. Because only three groups have reported the
investigation of connexin43 mutations so far in heterotaxy
syndromes, and because there was a striking difference in their
results, we sequenced that critical region of the connexin43
gene in our Hungarian patients with heterotaxy. DNA from 11 individuals
was amplified by polymerase chain reaction and
sequenced6 similarly to the reported
method.2 One case was familial and has been
reported elsewhere7 ; the other cases were
sporadic. Most of them were diagnosed prenatally by
echocardiography. In all cases, the
embryopathological examination of the fetus after induced abortion or
autopsy proved heterotaxy with asplenia or polysplenia and
cardiovascular anomalies. In 2 cases, there were no
available tissues for the examination, and only the parents' DNA was
sequenced. None of the examined DNA contained a mutation in the carboxy
terminal region of the connexin43 gene. We agree with Gebbia
et al that mutations in the terminal 400 bp of the
connexin43 coding region probably do not account for
heterotaxy cases. So far, 48 patients' DNA has been sequenced in
connection with connexin43 mutations. Six patients were
reported by Britz-Cunningham,2 12 by Penman
Splitt et al,5 19 by Gebbia et
al,1 and 11 by us. It is strange that only
patients reported by Britz-Cunningham et al carried a mutation in this
gene and even stranger that all of them carried one or two
connexin43 mutations whereas the other 42 patients did not
carry any mutation in that region of the connexin43 gene. On
the basis of the results of Gebbia et al and our observations, we
believe that it is more and more likely that the results reported by
Britz-Cunningham et al were a laboratory artifact. We should consider
changing the description of Ivemark syndrome in the McKusick catalogue
regarding connexin43 mutations.
References
1.
Gebbia M, Towbin JA, Casey B. Failure to
detect connexin43 mutations in 38 cases of sporadic and
familial heterotaxy. Circulation. 1996;94:1909–1912.
2.
Britz-Cunningham SH, Shah MM, Zuppan CW, Fletcher WH.
Mutations of connexin-43 gap junction gene in patients with heart
malformations and defects of laterality. N Engl J
Med. 1995;332:1323–1329.
3.
McKusick VA. Mendelian Inheritance in Man.
CD-ROM; Johns Hopkins University, September 29, 1995.
4.
Casey B, Ballabio A. Connexin43 mutations in sporadic
and familial defects of laterality. N Engl J Med. 1995;333:941–942.
5.
Penman Splitt M, Burn J, Goodship J. Connexin43
mutations in sporadic and familial defects of laterality. N
Engl J Med. 1995;333:941–942.
6.
Myöhänen S, Wahlfors J, Janne J. Automated
fluorescent genomic sequencing as applied to the methylation
analysis of the human ornithine decarboxylase gene. DNA
Seq. 1994;5:1–8.[Medline]
[Order article via Infotrieve]
7.
Cesko I, Hajdú J, Tóth T, Marton T, Papp C,
Papp Z. Ivemark syndrome with asplenia in siblings. J
Pediatr. 1997;130:822–824.[Medline]
[Order article via Infotrieve]
Department of Pathology,
Baylor College of Medicine,
Houston, Tex
We have read with interest the letter to the Editor of
Toth et al describing their inability to detect connexin43
(cx43) mutations in 11 cases of heterotaxy. The negative results of
Toth et al now brings to 78 the number of reported heterotaxy cases in
which no cx43 mutations could be found in the 200 base pairs containing
all of the nucleotide changes reported by Britz-Cunningham
et al.1 2 3 Mice either lacking or overexpressing
cx43 develop right-heart outflow obstruction, but the
complex cardiac and extracardiac malformations typical of heterotaxy
have not been observed.4 5 The absence of
animal-model data to support a role of cx43 in mammalian
left-right axis development as well as the inability of three
independent groups to detect cx43 mutations in a large
number of heterotaxy cases suggests the possibility of laboratory
artifact underlying the original detection of "mutations" reported
by Britz-Cunningham et al.
Family studies indicate that heterotaxy is likely to be quite
heterogeneous genetically.6 For
example, we have identified recently a gene for X-linked
heterotaxy,7 mutations in which appear to account
for only a minority of cases in males (K. Kosaki et al, unpublished
observations). Given this genetic heterogeneity, it was
surprising that Britz-Cunningham et al detected cx43
mutations in all of the heterotaxy cases that they studied.
We agree that the accumulating negative data counsel caution in drawing
connections between cx43 and heterotaxy, particularly in
such frequently consulted reference works as On-line Mendelian
Inheritance in Man (Internet address:
http://www.ncbi.nlm.nih.gov/Omim/). Reproduction of the
original results by an independent laboratory may be the most efficient
approach to resolving this issue.
References
1.
Gebbia M, Towbin J, Casey B. Failure to
detect connexin43 mutations in 38 cases of sporadic and
familial heterotaxy. Circulation. 1996;94:1909–1912.
2.
Penman-Splitt M, Tsai M, Burn J, Goodship J. Absence of
mutations in the regulatory domain of the gap junction protein connexin
43 in patients with visceroatrial heterotaxy. Heart. 1997;77:369–370.
3.
Britz-Cunningham S, Shah M, Zuppan C, Fletcher W.
Mutations of the connexin43 gap-junction gene in patients with heart
malformations and defects of laterality. N Engl J
Med. 1995;332:1323–1329.
4.
Reaume A, de Sousa P, Kulkarni S, Langille B, Zhu D,
Davies T, Juneja S, Kidder G, Rossant J. Cardiac malformation in
neonatal mice lacking Connexin43. Science. 1995;267:1831–1834.
5.
Ewart JL, Cohen MF, Meyer RA, Huang GY, Wessels A,
Gourdie RG, Chin AJ, Park SM, Lazatin BO, Villabon S, et al. Heart and
neural tube defects in transgenic mice overexpressing the Cx43 gap
junction gene. Development. 1997;124:1281–1292.[Abstract]
6.
Kosaki K, Casey B. Genetic aspects of human
left-right axis malformations. Semin Cell Dev Biol. In
press.
7.
Gebbia M, Ferrero GB, Pilia G, Aylsworth AS,
Penman-Splitt M, Bird LM, Bamforth JS, Burn J, Schlesinger D, Nelson
DL, Casey B. X-linked situs inversus and situs ambiguus
result from mutations in the zinc-finger transcription factor ZIC3.
Nat Genet. In
press.
© 1998 American Heart Association, Inc.
Correspondence
connexin43 Gene Mutations and Heterotaxy
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