Original Article
COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps
N Engl J Med 2007; 357:2687-2695December 27, 2007
- Abstract
Background
COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown.
Methods
We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1–COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects.
Results
We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV α1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries.
Conclusions
COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.
Media in This Article
Figure 1
Phenotypic Characterization of Patients with the Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome.Figure 2
Pedigrees and COL4A1 Mutations of Families 1, 2, and 3.Article Activity
- Article
Six alpha chains of type IV collagen — α1(IV) through α6(IV) — produce three networks of type IV collagen: α1.α1.α2(IV), α3.α4.α5(IV), and α5.α5.α6(IV). These three networks are the main component of basement membranes. Alpha chains of type IV collagen consist of an N-terminal 7S domain; a triple-helical collagenous domain, containing the classic Gly–Xaa–Yaa repeat amino acid sequence; and a C-terminal noncollagenous NC1 domain.1 The α1.α1.α2(IV) network is widely expressed in the body, whereas the α3.α4.α5(IV) and α5.α5.α6(IV) networks have a tissue-restricted expression. In the kidney, the α3.α4.α5(IV) network replaces the α1.α1.α2(IV) network during embryogenesis of the glomerular basement membrane, whereas the basement membrane of tubules and Bowman's capsules are composed mainly of a mixed α1.α1.α2(IV)–α5.α5.α6(IV) network.2
Alport's syndrome is caused by mutations in type IV collagen. The most common X-linked form is caused by mutations in COL4A5 (Online Mendelian Inheritance in Man [OMIM] number 301050), but 15% of cases of Alport's syndrome are due to autosomal recessive (or in rare cases, dominant) mutations affecting either COL4A3 or COL4A4 (OMIM number 203780 and OMIM number 104200, respectively).1 The clinical phenotype of Alport's syndrome correlates with the expression pattern of α3.α4.α5(IV). In addition, 50% of cases of familial benign hematuria have been attributed to mutations in COL4A3 or COL4A4.1
Mutations in COL4A1 have recently been identified in both a mouse model and families with porencephaly, a rare autosomal dominant condition characterized by cystic brain cavities and cerebral white-matter lesions.3-6 COL4A1 mutations have also been found in a single family with small-vessel disease affecting the brain and the eye.6,7
The widespread expression of the α1.α1.α2(IV) network suggests that COL4A1 mutations may lead to a systemic phenotype. We describe COL4A1 mutations in subjects from three families who have hereditary angiopathy with nephropathy, aneurysms, and muscle cramps, which we call the HANAC syndrome. The nephropathy consisted of persistent hematuria or bilateral, large cysts. The angiopathy affects both small vessels and large arteries and causes leukoencephalopathy, retinal arteriolar tortuosity, and intracranial aneurysms. All three COL4A1 mutations, localized in exons 24 and 25, affect glycine residues, interrupting the Gly–Xaa–Yaa amino acid repeat.
Methods
Clinical Evaluation
Written informed consent was obtained from all subjects or their parents. Phenotypic studies included clinical evaluation, urinalysis, measurement of serum creatinine levels and urinary protein excretion, estimation of the glomerular filtration rate with the use of the four-variable Modification of Diet in Renal Disease equation,8 abdominal ultrasonic tomography, abdominal computed tomography (CT) or renal magnetic resonance imaging (MRI), muscle testing and measurement of serum creatine kinase levels, funduscopic examination and fluorescein angiography, brain MRI, and cerebral magnetic resonance angiography or CT angiography.
Genetic-Linkage Analysis
Genomic DNA was extracted according to standard methods. For haplotype analyses, we used polymorphic microsatellite markers — D13S173, D13S126, D13S1315, and D13S261 — that span the genetic interval of the COL4A1–COL4A2 locus at 13q34.
Detection of Mutations
Primary fibroblasts were cultured from skin-biopsy specimens. Total RNA was isolated from the cultured fibroblasts with RNAwiz (Ambion). Complementary DNA (cDNA) was synthesized with the use of the Superscript first-strand synthesis system for the reverse-transcriptase–polymerase-chain-reaction assay (Invitrogen). Full-length COL4A1 cDNA was amplified with the use of 11 primer pairs, and both strands were sequenced. Family members and 150 ethnically matched controls were screened for mutations with the use of specific primers amplifying COL4A1 exon 24 or exon 25. (The sequences of all primers are listed in the Supplementary Appendix, available with the full text of this article at www.nejm.org.)
Electron Microscopy and Immunogold Electron Microscopy
Electron microscopy was performed as previously described.9 Immunogold electron microscopy was performed on ultrathin frozen sections of kidney-biopsy specimens as previously described.10 Sections were processed for indirect immunogold labeling with the use of rabbit antihuman α1(IV) and α2(IV) antibodies (dilution, 1:120) (Novotec).
Results
Phenotypic Evaluation
The phenotypic characteristics of affected subjects are shown in Figure 1Figure 1
Phenotypic Characterization of Patients with the Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome. and listed in Table 1Table 1
Clinical Characteristics of Families with the Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome..Family 1
In Family 1, the clinical phenotype was transmitted as an autosomal dominant trait (Figure 2AFigure 2
Pedigrees and COL4A1 Mutations of Families 1, 2, and 3.).9 All affected subjects presented with microscopic hematuria, muscle cramps with elevated creatine kinase levels, and bilateral retinal arteriolar tortuosity that caused repeated retinal hemorrhages (Figure 1J). Gross hematuria occurred in Subjects III-1, III-3, and IV-4; supraventricular cardiac arrhythmia occurred in Subjects II-2, III-1, and IV-1; and Raynaud's phenomenon occurred in Subjects III-1, III-3, IV-1, IV-2, and IV-4. All affected subjects had normal blood pressure.Renal CT revealed small, bilateral cysts in Subjects II-2, III-1, and III-3. Brain MRI revealed white-matter abnormalities and dilated microvascular spaces in Subjects III-1, III-3, IV-2, and IV-4 (Figure 1D). Aneurysms affected the intracranial segment of the right internal carotid artery in Subjects III-3 (Figure 1G), IV-2 (aneurysm diameter, 6 mm), and IV-4 (aneurysm diameter, 4 mm), and an aneurysm, 2 mm in diameter, was detected in the horizontal segment of the right middle cerebral artery in Subject IV-4. The results of cerebral imaging were normal for Subject IV-1 and were not available for Subject III-5. Subject III-3, who was 48 years of age at the time of imaging, had previously had a lacunar infarct of the brain stem.
Subjects IV-1 and IV-4 underwent kidney biopsy because of persistent microscopic hematuria. The tissue sections showed no abnormalities on light microscopy (Figure 1A, top), and immunofluoresence studies showed normal expression of COL4A1 (Fig. 1S, Panels C and D, in the Supplementary Appendix) and of COL4A3 and COL4A5 (reported previously9 for Subject IV-1 and not shown for Subject IV-4). The expression of laminin α5 and perlecan was normal (Fig. 2S, Panels A and B, in the Supplementary Appendix), but there was no apparent induction of laminin-5 and integrin β4 in the tubular basement membrane (data not shown). Electron-microscopical examination of the kidney-biopsy specimens from Subjects IV-1 and IV-4 revealed similar alterations of the basement membranes of the Bowman's capsule, tubules, and interstitial capillaries (Figure 1A and Figure 3A 3B, 3C, 3D, and 3EFigure 3
Abnormalities of the Renal Basement Membrane in Subjects IV-1 and IV-4, Family 1.,). These alterations were characterized by irregular thickening, splitting in multiple layers, and electron-lucent areas. Numerous focal interruptions of the basement membrane were seen in interstitial capillaries (Figure 3A). In contrast, the glomerular basement membrane had a normal appearance and thickness (Fig. 1S, Panels A and B, in the Supplementary Appendix).9 Immunoelectron microscopy showed normal expression of α1.α1.α2(IV) trimers in the glomerular basement membrane (Fig. 1S, Panel E, in the Supplementary Appendix) and in the tubular and interstitial capillary basement membranes, except in electron-lucent areas (Figure 3G).Similar alterations of the basement membrane, including duplications, were seen in the skin at the dermoepidermal junction in Subjects III-3 and IV-4 (Figure 4A and 4BFigure 4
Abnormalities of the Skin Basement Membrane in Families 1 and 3.). In dermal arterioles, vascular smooth-muscle cells were dissociated, with abnormal spreading of the basement membrane (Figure 4E and 4F). The muscle ultrastructure was normal.Family 2
In Family 2, the affected subjects (Figure 2A) presented with bilateral retinal arteriolar tortuosity, which caused hemorrhages in Subjects I-1, II-1, and II-3 (Figure 1K). Clinical evaluations and genetic studies were performed in Subject II-1 and in his two daughters (25-year-old Subject III-1 and 21-year-old Subject III-2). Subject II-1 had mild renal failure (glomerular filtration rate, 56 ml per minute per 1.73 m2 of body-surface area), without proteinuria or hematuria, normal blood pressure, and bilateral large cysts (Figure 1B). The size of the left kidney was normal (long-axis length, 113 mm), but the lower pole of the right kidney (long-axis length, 138 mm) was deformed by a massive cyst (90 mm in diameter). Subject II-1 also had periventricular white-matter abnormalities (Figure 1E). Subject III-2 had neither renal abnormalies nor a brain lesion, but she did have elevated creatine kinase levels, without muscle cramps, and an aneurysm of the right internal carotid artery, 2 mm in diameter (Figure 1H). Funduscopic, renal, and cerebral evaluations in Subject III-1 were normal.
Family 3
In Family 3, retinal arteriolar tortuosity and hemorrhages were found in Subjects I-1 and II-3 (Figure 1L and Figure 2A). Data from detailed investigations were available for Subject II-3, in whom muscle cramps that limited exercise developed during childhood. The serum creatine kinase level was persistently elevated, and electromyograms were normal. Renal evaluations revealed mild renal failure (glomerular filtration rate, 52 ml per minute per 1.73 m2) — without hypertension, proteinuria, or hematuria — and bilateral, large cysts, the largest of which was 140 by 84 mm and was in the left kidney (Figure 1C). A large hepatic cyst (91 by 65 mm) was also detected (Figure 1C). Fifteen years earlier, ultrasonography had revealed smaller cysts in the left kidney (50 mm in diameter) and in the liver (40 mm in diameter). Subject II-3 had posterior leukoencephalopathy (Figure 1F) and three aneurysms (2, 6, and 8 mm in diameter) in the right internal carotid artery, Raynaud's phenomenon, and paroxysmal supraventricular cardiac arrhythmia. Funduscopic, renal, and cerebral evaluations were normal in Subjects II-1 and III-2.
A skin biopsy was performed in Subjects II-3 (with the COL4A1 mutation) and III-2 (without the mutation) to determine whether a skin-membrane disease (basalopathy) was present. Subject II-3 had alterations of the basement membrane at the dermoepidermal junction and in vessel walls (Figure 4C and 4G), which were similar to those seen in Subjects III-3 (Figure 4A and 4E) and IV-4 (Figure 4B and 4F) in Family 1. The ultrastructure of the skin was normal in Subject III-2 (Figure 4D and 4H).
Genetic Analyses
Linkage analysis indicated that all affected subjects in Family 1 shared a common haplotype at the COL4A1–COL4A2 locus (data not shown). Sequence analysis of COL4A1 cDNA from Subject IV-1 revealed the heterozygous missense mutation c.1493G→T in exon 24, responsible for a glycine-to-valine substitution (p.Gly498→Val) (Figure 2A). This mutation was present in all affected subjects in Family 1 who were alive. Subjects II-1 and III-2 from Family 2 had the missense mutation c.1555G→A in exon 25, leading to a glycine-to-arginine substitution (p.Gly519→Arg) (Figure 2A). In Family 3, the missense mutation c.1583G→A was detected in exon 25, leading to the substitution of glutamic acid for glycine (p.Gly528→Glu) (Figure 2A). No mutations were found in the 150 ethnically similar control samples (representing 300 chromosomes). The three affected glycine residues are located near one another in the collagenous domain, at sites that are highly conserved (Figure 2B). The Gly498 and Gly528 residues are located at the C-terminal end of an identical amino acid sequence (Gly–Glu–Pro–Gly–Ala–Lys–Gly). This sequence is not present in other segments of the COL4A1 protein and is conserved among vertebrate species (Figure 2B).
Discussion
We have identified three mutations of the COL4A1 gene that appear to be associated with a systemic disease we call the HANAC syndrome. All three mutations affect glycine residues that are close to each other, located in exons 24 and 25, suggesting that these exons may encode critical functional domains of the COL4A1 triple helix.
The identification of COL4A1 mutations in patients with the HANAC syndrome extends the spectrum of diseases associated with heterozygous COL4A1 mutations. Previously reported mutations are associated with dominant small-vessel disease affecting only retinal vessels and the brain.3-6 In contrast, the HANAC syndrome affects the kidney, muscle, and cardiovascular system, including retinal and cerebral vessels. Moreover, the condition affects large vessels (through intracranial aneurysms). The HANAC syndrome is phenotypically distinct from hereditary endotheliopathy with retinopathy, nephropathy, and stroke, which maps to chromosome 3p21.11
In Family 1, hematuria was consistently associated with the other manifestations of the HANAC syndrome. Severe ultrastructural defects of the basement membrane in Bowman's capsules, tubules, and interstitial capillaries were detected in both affected subjects studied. Similar alterations were observed in skin basement membrane; together with the clinical phenotype, this finding points to widespread basement-membrane disease. Mice that have Col4a1 mutations such as those related to bruising at birth (Col4a1 +/Bru) or to retinal arteriolar wiring (Col4a1 +/Raw) also have focal basement-membrane disruptions in multiple tissues and splitting of the basement membrane of the Bowman's capsule.12 In contrast, the glomerular basement membrane has a normal appearance in patients with the HANAC syndrome, in Col4a1 +/Bru mice, and in Col4a1 +/Raw mice. These findings can be explained by the predominance in adults of the α1.α1.α2(IV) trimer in most basement membranes, except for that of the glomerulus. The anomalies of the tubular basement membrane are reminiscent of the “basket-weave” appearance of the glomerular basement membrane in patients with Alport's syndrome. We hypothesize that the hematuria seen in Family 1 may be the result of defects in the basement membrane of the tubules and the peritubular capillaries.
In Families 2 and 3, the phenotype was characterized by bilateral renal cysts and mild renal failure. The cysts in the renal poles were very large, although the overall size of the kidney remained roughly preserved. The absence of renal cysts in Subject III-2 in Family 2, who was 20 years old, might be related to the development of cysts with age. Small bilateral cysts were also found in older members of Family 1. The cystic phenotype is different from that in polycystic kidney diseases or medullary cystic kidney disease. Cyst formation is usually associated with abnormal remodeling of the extracellular matrix and altered composition of the basement membrane.13,14 Kidney biopsy was not performed in affected subjects from Families 2 and 3 because of the presence of cysts. However, a skin-biopsy specimen from Subject II-3 in Family 3 showed basement-membrane alterations similar to those in affected subjects in Family 1. These findings, together with the previously reported association of a hypomorphic mutation in the laminin α5 gene with polycystic kidney disease,15 indicate the importance of components of the basement membrane in cyst formation.
The varied presentation of our patients, who had cysts, hematuria, or even an absence of renal anomalies, mirrors the variable renal phenotype seen in mice with Col4a1 mutations.6,12,16 Such variability might be explained by the variable location of the identified mutations, with those in exon 25 producing the cystic phenotype. In addition, the role of modifier genes in the ocular phenotype has recently been demonstrated in Col4a1 +/Δex40 mice.16
All affected subjects in the three families had the typical retinal arteriolar tortuosity previously reported in both mice and humans.6,7 However, the systemic angiopathy also affected large vessels, resulting in intracranial aneurysms. A possible factor in the pathophysiological characteristics of intracranial aneurysms is the disruption of the extracellular matrix of the arterial wall.17,18 Several candidate genes encoding matrix proteins have been identified in linkage studies19 and analyses of single-nucleotide polymorphisms,20 but causative genes have not yet been identified, with the exception of COL3A1 in Ehlers–Danlos syndrome type IV21 and the polycystic kidney disease 1 gene (PKD1).22 Our results add COL4A1 to the short list of genes involved in familial intracranial aneurysms.19
The p.Gly498→Val and p.Gly528→Glu mutations identified in Families 1 and 3 are associated with muscle cramps. Such cramps might involve transient ischemia or microhemorrhages in the microvasculature or altered skeletal-muscle function linked to defective interaction of mutant COL4A1 with muscle fibers or other matrix components, as observed in Bethlem myopathy (OMIM number 158810).23,24
We think that the phenotype may be caused by dominant-negative effects of the mutations, a speculation that is supported by findings from several animal models.3,6,12,25 Missense mutations of the COL4A1 and COL4A2 orthologues in Caenorhabditis elegans are associated with a defect in the composition of extracellular-matrix proteins related to the retention of collagen strands in the cytoplasm.26 Although we found neither retention of the α1.α1.α2(IV) trimer in endothelial cells nor a substantial decrease of its expression in the basement membrane, the mutant protein might compete with secretion or integration of the wild-type protein in the basement membrane or might affect the interaction with other basement-membrane components.
In conclusion, COL4A1 mutations appear to be responsible for a systemic basement-membrane disease. Diagnosis of the HANAC syndrome could be considered in families with unexplained, autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps; such consideration would involve funduscopic examination and a search for COL4A1 mutations.
Supported by grants from INSERM, Université Pierre et Marie Curie, Université Paris Descartes, and Association pour l'Utilisation du Rein Artificiel (AURA). Dr. Van Agtmael is the recipient of a Cardiovascular Research Initiative Wellcome Trust Fellowship.
No potential conflict of interest relevant to this article was reported.
We thank E. Tournier-Lasserve (INSERM Unité 740) for the gift of the COL4A1–COL4A2 microsatellite markers, M.C. Gubler (INSERM Unité 574) for helpful discussions, C. Combe (Department of Nephrology, University of Bordeaux) for contributions to the clinical evaluation of Family 1, C. Jouanneau and F. Fasani (INSERM Unité Mixte de Recherche Scientifique 702) for technical assistance, and the families for their participation in the study.
Source Information
From INSERM Unité 702 (E.P., B. Mougenot, M.C.V., P.R.); Université Pierre et Marie Curie, Paris 6, Unités Mixtes de Recherche Scientifique 702 (E.P., M.C.V., P.R.) and 582 (M.F.); Assistance Publique–Hôpitaux de Paris, Hôpital Tenon (E.P., S.A., B. Marro, E.R., P.R.), Hôpital Avicenne (C.P.), Hôpital Pitié–Salpêtrière (M.F.), and Hôpital Necker (C.A.); INSERM Unité 574 (O.G., C.A.); Center of Ophthalmology, Paris 15 (S.Y.C.); INSERM Unité 582 (M.F.); and Université Paris Descartes, Faculté de Médecine René Descartes, Unité Mixte de Recherche Scientifique 574 (C.A.) — all in Paris; Université Lille 2 (T.D.) and Centre Hospitalier Régional Universitaire Lille (M.D.) — both in Lille, France; University of Edinburgh, Queens Medical Research Institute, Edinburgh (T.V.A.); and Medical University of Vienna, Clinical Institute of Pathology, Vienna (D.K.).
Address reprint requests to Dr. Plaisier at the Department of Nephrology and INSERM Unité 702, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France, or at emmanuelle.plaisier@tnn.aphp.fr.
Dr. Roullet is deceased.
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