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Human Molecular Genetics Pages 1565-1571  

Two rights make a wrong: human left-right malformations
Introduction
Terminology Of Abnormal Left-Right Asymmetry
Syndromic LRA Malformations: Immotile Cilia Syndrome (ICS) And Kartagener Syndrome
Epidemiology
Anatomical Variation
Familial Heterotaxy: Inheritance Patterns And Phenotypic Variability
Vertebrate Models Of LRA Development
Molecular Genetics Of Human LRA Malformations
Considerations For The Future
Acknowledgements
References

Two rights make a wrong: human left-right malformations

Two rights make a wrong: human left-right malformations

Brett Casey*

Department of Pathology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA

Received May 18, 1998

Like all vertebrates, humans establish anatomical left-right asymmetry during embryogenesis. Variation from this normal arrangement (situs solitus) results in heterotaxy, expressed either as randomization (situs ambiguus) or complete reversal (situs inversus) of normal organ position. Familial heterotaxy occurs with autosomal dominant, recessive and X-linked inheritance. All possible situs variants, solitus, ambiguus and inversus, can appear among some heterotaxy families. Positional cloning has led to the identification of a gene on the X chromosome responsible for some cases of human heterotaxy. Additional candidate genes have emerged from recent studies of left-right axis development in chick, frog and mouse, which have begun to elucidate a tightly regulated genetic cascade that differentiates the left and right sides prior to the appearance of morphological asymmetry.

INTRODUCTION

Standing to sing the national anthem signals the imminent first pitch of most baseball games in the USA. Many in the crowd will have placed their right hand (or their cap, respectfully removed from its usual resting place) over the left side of their chest, where the heartbeat feels strongest. This display of nationalism unwittingly demonstrates something fundamental about human anatomy: although bilaterally symmetrical externally, we have internal left-right asymmetry whose overall direction is the same for us all.

Malformations result when the process of left-right axis (LRA) specification goes awry during embryogenesis. The following discussion reviews the terminology, manifestations and genetics of LRA malformations, as well as the impact of studies in chick, frog and mouse on our understanding of LRA specification gone wrong in Homo sapiens.

TERMINOLOGY OF ABNORMAL LEFT-RIGHT ASYMMETRY

One finds a confusing array of terms in the literature describing human LRA malformations. Most authors agree to designate the normal left-right anatomical arrangement as situs solitus. Mirror-image reversal of all asymmetrical structures has been given a variety of labels, situs inversus, complete or total situs inversus, situs inversus totalis and situs inversus viscerum. When the entire anatomical left-right axis is neither normal nor mirror-image reversed, the resulting phenotype has been called situs ambiguus, partial situs inversus, heterotaxy or heterotaxia (sometimes accompanied by the adjective `visceral'), laterality or isomerism sequence, and Ivemark, asplenia or polyasplenia syndrome. A search through Online Mendelian Inheritance in Man using these terms as search words uncovers descriptions of essentially the same phenotype, non-syndromic LRA malformations, in four different entries: heterotaxy, X-linked visceral (306955); laterality defects, autosomal dominant (601086); asplenia with cardiovascular anomalies (208530); and situs inversus viscerum (207100).

This review uses a somewhat heretical nomenclature. The term situs and its accompanying modifiers is reserved to summarize the left-right anatomy of the entire organism: situs solitus for normal, situs inversus for complete, mirror-image reversal of all asymmetrical structures and situs ambiguus for any other abnormality of LRA development. Positional malformations within situs ambiguus individuals are described using the words right, left and midline, as in `right-sided stomach and spleen', rather than `abdominal situs inversus'. The term heterotaxy, derived from the Greek meaning, `other arrangement', is used as a name for the disease whose primary manifestation is abnormal LRA specification, regardless of the final anatomical derangement (situs ambiguus or situs inversus). Thus, kindreds with multiple affected individuals, perhaps some situs ambiguus and some situs solitus, are said to have familial heterotaxy.

SYNDROMIC LRA MALFORMATIONS: IMMOTILE CILIA SYNDROME (ICS) AND KARTAGENER SYNDROME

Sometimes LRA malformations arise as one variable manifestation of a broader spectrum of defects. By far the most common of these so-called syndromic LRA malformations is situs inversus, occurring as one manifestation of ICS (1). Affected individuals suffer from chronic respiratory tract infections and from a variable combination of infertility (in males), chronic ear infections and decreased or absent sense of smell. These problems arise as a result of defective cilia and flagella, hence the diagnosis ICS. The cilia are functionally abnormal and electron microscopy usually reveals absence or abnormalities of the dynein arms connecting the nine pairs of microtubules.

Almost all familial occurrences of ICS are limited to affected offspring of unaffected (and sometimes related) parents with no apparent gender bias, hence the inference of autosomal recessive inheritance. All affected individuals harbor the ciliary and flagellar defects, but only about half are situs inversus (and thus are said to have Kartagener syndrome), while the remainder are situs solitus. It has been thought that situs ambiguus is extremely rare among individuals with ICS (2-4), but a relatively recent study found cardiac malformations in 12% of affected individuals (5). In general, however, there appears in ICS to be a randomization of the overall direction of left-right asymmetry to a final pattern of either situs solitus or situs inversus. The relationship between the ciliary defects and LRA formation has yet to be discovered.

EPIDEMIOLOGY

It has been estimated that situs inversus occurs with an incidence of 1/8000-1/25 000 live births, with ~1/5-1/4 of cases associated with underlying ICS (1). These figures may underestimate the true incidence of situs inversus, since by itself a mirror-image reversal of left-right asymmetry would pose no detriment to the affected individual. Incidence figures for situs ambiguus have been provided through epidemiological studies of congenital cardiovascular disease. The Baltimore-Washington Infant Study estimated an incidence of 1.44/10 000 for all cardiac defects associated with left-right asymmetry malformations (cardiac and/or non-cardiac), including corrected (levo) transposition of the great arteries (i.e. l-TGA with ventricular inversion) (6). Again, these figures may underestimate the true incidence of situs ambiguus because cases of LRA malformations with normal hearts or those with clinically silent cardiac malformations would not have been ascertained in this study.

ANATOMICAL VARIATION

Situs ambiguus describes an overall anatomical arrangement that suggests a randomization of left-right position along the superior-inferior axis (anterior-posterior in quadripeds). Any structure with left-right asymmetry can be normal, completely reversed or neither. The heart appears particularly sensitive to perturbation in normal left-right positional information, because most children recognized to be situs ambiguus manifest complex cardiac defects. The anatomy of each lung can be that of either the normal right or normal left. In the abdomen, the spleen is often (but not always) abnormal in position, number or both. The liver is often on the midline or reversed in the relative sizes of its right and left lobes.

Gastrointestinal malrotation [more precisely `intestinal rotation and fixation abnormalities' (IRFA)] has probably been an under-appreciated manifestation of LRA malformations. Individuals with IRFA are at risk of developing acute volvulus, which can be fatal even if recognized and treated promptly. For this reason, some authors recommend that situs ambiguus individuals undergo evaluation for IRFA (7), which, if present, can be treated prophylactically by the laparoscopic Ladd procedure (8).

Malformations other than those of obvious asymmetrical positioning are seen among individuals with situs ambiguus. These include hindgut malformations (e.g. anal atresia or stenosis), which occur more often in males and in particular in familial cases with inheritance patterns consistent with X chromosome linkage. Outside the midline, urinary tract anomalies (renal agenesis and hypoplasia, ureteral malformations) are also seen with some frequency (9).

FAMILIAL HETEROTAXY: INHERITANCE PATTERNS AND PHENOTYPIC VARIABILITY

Familial situs inversus outside the setting of ICS has been reported a few times, with inheritance patterns suggesting an autosomal recessive trait (10-12). In one family, four individuals across three generations are situs inversus but do not have ICS. The degree of consanguinity among the relevant matings is quite high, so the inheritance may still be autosomal recessive rather than dominant (13).

The usual descriptions of familial situs ambiguus are of two or more affected siblings born to normal, often consanguineous parents. Both autosomal dominant and X-linked inheritance have been thought to be distinctly uncommon, based on the infrequency with which they were reported in the literature and, for the latter, because of relatively equal numbers of affected males and females among sporadic cases. Recent reports, however, suggest that autosomal dominant inheritance may be much more common than previously supposed and that situs inversus and situs ambiguus can indeed occur in the same family (14-16). Figure 1 shows pedigrees of four kindreds that we have studied in some detail. All share the characteristic that situs inversus and situs ambiguus are present among different members of the same family. Furthermore, obligate carriers who are situs solitus appear in each family. Only family LR14 segregates a mutation in the X-linked zinc-finger transcription factor ZIC3 (see below); linkage to the ZIC3 region has been excluded in the remaining families (M. Gebbia and B. Casey, unpublished data).


Figure 1. Pedigrees of familial heterotaxy.

Notable in families LR10 and LR11 are isolated heart malformations appearing in relatives of individuals with heterotaxy. This association has been noted by many other observers (16-20) and leads to an intriguing hypothesis: could some cases of sporadic, isolated heart malformations be manifestations of abnormal LRA development and that for some reason the other organs were unaffected? Testing of this hypothesis awaits the identification of genes mutated in individuals with indisputable heterotaxy and the search for mutations in these genes among individuals with isolated, heterotaxy-like heart malformations. Alternatively, there may be cardiac-specific genes downstream of more global left-right organizers that, if mutated, would lead to cardiac LRA malformations but spare other organ systems.

VERTEBRATE MODELS OF LRA DEVELOPMENT

Several recent reviews summarize the studies in chick, Xenopus and mouse that have dramatically expanded our understanding of LRA specification in vertebrates (21-23). The TGF[beta] family member Vg1 appears to initiate LRA formation at the 16 cell stage of Xenopus, well before the appearance of Spemann's organizer. Injection of BVg1 (a BMP-2-Vg1 fusion construct ensuring that Vg1 is processed) mRNA into the right dorsovegetal cell of the 16 cell stage embryo results in randomized expression of Xnr-1 and subsequent randomization of cardiac looping (24,25).

Table 1. Genes implicated in vertebrate LRA specification by expression/misexpression studiesa
Gene Zebrafish Xenopus Chick Mouse Mouse LRA in null Humanb References
Vg1   M         24,25
[beta]-catenin   M     el 3p2 60,61
siamois   M         60
activin[beta]B     R;M   nl   30
cActRIIa     R S nl   21,26
follistatin     R S nl   c
cWnt8c     R       21
HNF3[beta]     L S el 20p11 21,26
HGF/SF     L S nl   21,62,64
shh M   L;M S nl   21,26,30,65
ptc     L S el 9q22 30,66,67
nodal   L;M L;M L* el 10q22 24-30,68-70
lefty-1       L*     36
lefty-2       L     36,37
snail     R       70
HAND1       L* ?abnl ?5q;17p 71-73
flectin     L       74
hLAMP1     L       75
JB3     R       75
BMP4 R     S el 14q2 62,76
aR, right-sided asymmetrical expression; L, left-sided asymmetrical expression (*altered expression in iv and inv backgrounds); S, only symmetrical expression detected to date; M, misexpression alters normal or predicted LRA specification; nl, normal LRA morphology; el, early embronic lethality precludes assessment of LRA morphology; ?abnl, LRA may be abnormal.
bCytogenetic location of human homolog (if known) for those genes with embryonic lethal or abnormal LRA phenotype in null mice.
cM. Levin, personal communication.

Xnr-1 is the Xenopus homolog of chick cNR-1 and mouse nodal. In their respective organisms these genes are expressed predominantly in the lateral plate mesoderm along the left side of the developing embryo (26-29). This asymmetrical expression was first detected in chick, where activin[beta]B, activin receptor cAct-RIIa, follistatin, HNF3[beta], cWnt-8c, HGF/SF, sonic hedgehog (shh) and patched (ptc) are also expressed asymmetrically at or near Hensen's node (the Spemann organizer equivalent in chick) prior to the appearance of left-sided cNR expression (21,26,30). Of these avian genes, however, only nodal is asymmetrically expressed in mouse (28,31-35). Also expressed in a left-sided pattern in the mouse are lefty-1 and lefty-2, two newly described TGF[beta] family members (36,37).

Although several genes are asymmetrically expressed in chick, there is a relative paucity of genetic evidence supporting their involvement in vertebrate LRA formation. Mice homozygous for null mutations in any of these genes either die early in embryonic development or develop normal left-right asymmetry (Table 1). Surprisingly, however, double heterozygotes for nodal and HNF3[beta] alleles manifest left-right asymmetry defects (28). The results suggest an interaction between these molecules and provide strong genetic evidence for their involvement in LRA formation. Most recently, mice deficient in the activin receptor ActRIIB have been shown to manifest complex heart malformations and other visceral anomalies typical of situs ambiguus (38).

The most extensively studied murine model of LRA development is the spontaneous mutant iv (situs inversus viscerum). Approximately 30% of iv/iv mice display situs inversus, 30% situs solitus and the remainder situs ambiguus (39). A candidate gene for iv, left-right dynein (lrd), has been identified in which a missense amino acid substitution appears only in iv alleles (40). Identification of the iv gene as a dynein implicates microtubule arrays in the generation of left-right asymmetry. The protein encoded by lrd may be functioning as a microtubule motor, driving intracellular localization of transcript(s) and/or protein(s) that becomes left-right asymmetrical after cell division (23,40,41).

Another murine model, inversion of embryonic turning (inv), has been developed by insertional mutagenesis and results in a reversal of left-right asymmetry in >90% of homozygous transgenic mice (42). Normal asymmetrical expression of nodal and lefty-1 is disrupted in both iv and inv homozygotes (27,28,36), suggesting that both iv and inv function upstream of these TGF[beta] family members in LRA specification. Additional information for these as well as other mouse models is given in Table 2.

MOLECULAR GENETICS OF HUMAN LRA MALFORMATIONS

A small number of chromosomal abnormalities associated with situs ambiguus have been reported and may provide clues to the location of genes involved in LRA development (43-50). None of the candidate LRA genes identified in other organisms has been shown to map to one of the human cytogenetic breakpoints except one: nodal is located on mouse chromosome 10 in a region syntenic to human chromosome 10q21-q23, where a do novo interstitial deletion has been detected in an individual with situs ambiguus and midline malformations (49). Analysis of polymorphic microsatellites flanking human NODAL in the affected individual and her parents indicates that this gene is included within the deleted region (K. Kosaki and B. Casey, unpublished data). This observation lends further support to the hypothesis that NODAL mutations may contribute to the pathogenesis of some human LRA malformation cases (see below).

Positional cloning has proven effective in the identification of one molecular genetic cause of human LRA malformations (51-53). One sporadic and four familial cases of LRA malformations were found to harbor intragenic mutations in ZIC3, an X-linked zinc-finger transcription factor originally identified as one of four similar genes in mice. All five mutations (two null, one frameshift and two missense) were found in the region encoding the five highly conserved zinc fingers. In addition, another affected male was shown to have a submicroscopic deletion in Xq26.2 that encompassed the entire ZIC3 coding region (52).

All of the males with a ZIC3 mutation were situs ambiguus. Furthermore, each ZIC3 mutant allele was associated with hindgut anomalies (e.g. anal stenosis) in at least one affected individual. No ZIC3 coding region mutations have been identified in another 35 males with situs ambiguus, none of whom had anal, lumbosacral or other midline anomalies (K. Kosaki and B. Casey, unpublished data). These results suggest that hindgut anomalies accompanying abnormal LRA specification may be a phenotypic marker for an underlying ZIC3 mutation.

Table 2. Mouse models of LRA specification
Locus Gene LRA phenotypea Humanb References
Dh ? Asplenia, altered venous asymmetry (abdomen) in Dh/+ and Dh/Dh ?2q 77,78
Ft ? e.l. (10.5 d.p.c.), random embryonic turning, situs ambiguus; abnl lefty, nodal expression in -/- ?16q 79-81
inv ? [ge]90% situs inversus, [le]10% situs ambiguus, abnl lefty, nodal expression in -/- ?9q 42
iv lrd Situs inversus/ambiguus/solitus, abnl lefty, nodal expression in -/- ?7p 40
legless lrd? As inv ?7p 82
SIL Situs ambiguus, bilateral nodal, lefty expression in -/- 1p32 c
MGAT1 e.l. (10.5 d.p.c.), random embryonic turning, situs ambiguus in -/- 5q31 83
actRIIb situs ambiguus in -/- 3p22 38
HNF3[beta]; nodal +/- situs ambiguus in double heterozygotes 20p11; 10q22 28
Abbreviations as in Table 1.
aPhenotype in homozygous null mice unless otherwise specified; other malformations may be present.
b?, region in human syntenic to that in which gene has been mapped in mouse.
cM. Kuehn, personal communication.

Affected females have been described in one family segregating a ZIC3 mutation (family LR14, Fig. 1) (53). Three of seven carrier females are situs inversus, while each of the affected males is situs ambiguus. Two of the situs inversus females had anal anomalies and the other has a duplicated right ureter. ZIC3 mutations in situs ambiguus females, sporadic or familial, have not been identified to date.

Murine Zic3 is one of four gene-family members originally identified by Aruga et al. (54-56). The Zic genes are most closely related to Drosophila odd-paired, a segment polarity gene that is negatively regulated by dpp (a TGF[beta] family member) and is required for timely activation of wingless (homologous to the vertebrate Wnt genes; 57,58). Furthermore, as a family the Zic genes have significant homology to the Gli-cubitus interruptus class of zinc-finger transcription factors, which have been shown to be involved in (sonic) hedgehog signalling in vertebrates and Drosophila respectively (for a review see ref. 59). Recall that all of these signalling pathways, hedgehog, TGF[beta] and Wnt, have been implicated in vertebrate LRA specification. The role that ZIC3 plays in this process remains to be elucidated.

ZIC3 mutations account for only a small percentage of human LRA malformations. What of the other cases? Not surprisingly, studies in vertebrate model systems may provide excellent candidate genes as targets for mutation analysis. Particularly compelling as candidates are those genes whose role in LRA specification has been confirmed in mice: HNF3[beta], ACTRIIB, nodal, lefty-1 and -2 and lrd. Recently we identified missense amino acid substitutions in some of these genes among LRA malformation cases (M.T. Bassi et al., unpublished data). Intriguingly, several affected individuals are multiple, usually double, rarely triple, heterozygotes for LRA gene mutations.

CONSIDERATIONS FOR THE FUTURE

Clinical and molecular studies suggest that human LRA malformations are genetically heterogeneous and quite variable in their manifestations. Several important questions remain unanswered. To what extent will genes implicated in LRA development in model organisms be responsible for human disease? Will multigenic inheritance account for some cases of human heterotaxy? Are some complex, isolated heart malformations actually unrecognized manifestations of aberrant LRA development? Will the positional cloning of additional human disease genes enlarge our general understanding of vertebrate LRA development? Based on recent results, one may hope that answers to these questions will be provided in the near future.

ACKNOWLEDGEMENTS

We thank the many families and clinicians who have made these studies possible. Support from the Core Facilities of the Mental Retardation Research Center (P30 HD24064) is gratefully acknowledged. This work was supported in part by grants from the NIH (5K08HD01078 and 1R03HD36003) and by Grants-in-Aid from the American Heart Association Texas Affiliate (94G-894) and National Center (96015660).

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*To whom correspondence should be addressed. Tel: +1 713 798 7941; Fax: +1 713 798 5838; Email: bcasey@bcm.tmc.edu

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