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Novel COL4A3 Mutations in African American Siblings With Autosomal Recessive Alport Syndrome
CASE REPORT Novel COL4A3 Mutations in African American Siblings With Autosomal Recessive Alport Syndrome Christine Cook, MD,1 Christopher A. Friedrich, MD, PhD,2 and Radhakrishna Baliga, MD1 We describe a novel mutational study in 2 African American siblings with autosomal recessive Alport syndrome. Both siblings were compound heterozygotes for 2 abnormal DNA sequences in exon 49 of the COL4A3 gene, p.Arg1496X (CGA¡TGA) and p.Arg1516X (CGA¡TGA). These are nonsense mutations in the noncollagenous domain resulting in premature termination codons and have not been previously reported. In an African American population in which autosomal recessive Alport syndrome is rarely seen, complete sequencing of the COL4A3 and COL4A4 genes may be necessary to identify the underlying mutation and confirm the diagnosis. Am J Kidney Dis 51:e25-e28. © 2008 by the National Kidney Foundation, Inc. INDEX WORDS: Alport syndrome; kidney failure; mutation detection; kidney transplant.
A
lport syndrome is a progressive hereditary nephropathy often associated with extrarenal manifestations, including sensorineural deafness and/or ocular abnormalities.1 It is a genetically heterogeneous disease caused by mutations in type IV collagen of the basement membrane. Inheritance patterns include X-linked dominant (80%), autosomal recessive (15%), and autosomal dominant (5%).2 The autosomal recessive form is caused by mutations in either the COL4A3 or COL4A4 collagen genes. It rarely was reported in African Americans. We describe novel nonsense mutations in the COL4A3 gene in African American siblings who are compound heterozygotes for autosomal recessive Alport syndrome.
CASE REPORTS Patient 1 A 14-year-old African American girl presented with a 2-day history of headaches. Her review of systems was negative except for a 1-year history of progressive hearing loss. On examination, blood pressure was 168/119 mm Hg, with normal fundi and 1⫹ pitting edema of the lower extremities. Serum creatinine level was 4.3 mg/dL (380 mol/L), and blood urea nitrogen level was 30 mg/dL (10.7 mmol/L). Estimated creatinine clearance was 21 mL/min/ 1.73 m2 (0.35 mL/s). On urinalysis, there was 3⫹ protein and moderate blood. Urinary protein-creatinine ratio was 4.0 (normal, ⬍0.2). Twenty-four–hour urine protein excretion was 5.8 g. Serum total protein level was 7.3 g/dL (73 g/L), and albumin level was 3.9 g/dL (39 g/L). Serum cholesterol level was increased at 251 mg/dL (6.49 mmol/L). A renal biopsy specimen showed changes consistent with Alport syndrome. Audiometry confirmed the presence of moderate bilateral sensorineural hearing loss. A skin biopsy specimen showed uninterrupted staining of epidermal basement membrane for the ␣5 chain of type IV collagen (CE
Kashtan, Minneapolis, MN). The patient was started on calcium channel blocker therapy. Peritoneal dialysis therapy was initiated 5 months later. One year after her initial presentation, she received a living related donor kidney transplant from her father. Twenty-seven months after transplantation, both the donor and recipient have had no proteinuria or hematuria. Renal function of the recipient remains stable with a serum creatinine level of 1.4 mg/dL (124 mol/L), blood urea nitrogen level of 15 mg/dL (5 mmol/L), and urinary protein-creatinine ratio of 0.1.
Patient 2 The 11-year-old sister of patient 1 was evaluated for hematuria and a 2-month history of intermittent headaches. She had no known hearing deficit. Blood pressure was 133/80 mm Hg, and physical examination findings were unremarkable. Serum creatinine level was 0.7 mg/dL (62 mol/L), and blood urea nitrogen level was 7 mg/dL (2.5 mmol/L). Estimated creatinine clearance was 124 mL/min/ 1.73 m2 (2.07 mL/s). On urinalysis, there was 3⫹ protein and large blood. Twenty-four–hour urine protein excretion was 2.5 g. Total serum protein level was 5.0 g/dL (50 g/L), and albumin level was 3.4 g/dL (34 g/L). Serum cholesterol level was increased at 253 mg/dL (6.54 mmol/L). The renal biopsy specimen showed findings consistent with Alport syndrome. Audiometry showed bilateral sensorineural hearing loss. Treatment with an angiotensin-converting enzyme
From the 1Department of Pediatrics and 2Department of Preventive Medicine, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, MS. Received and accepted in revised form January 31, 2008. Originally published online as doi:10.1053/j.ajkd.2007.09.028 on April 2, 2008. Address correspondence to Radhakrishna Baliga, MD, Department of Pediatrics, 2500 North State St, Jackson, MS 39216. E-mail: [email protected] © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5105-0001$34.00/0 doi:10.1053/j.ajkd.2007.09.028
American Journal of Kidney Diseases, Vol 51, No 5 (May), 2008: e25-e28
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Cook, Friedrich, and Baliga Direct DNA sequencing in the older sister indicated 2 heterozygous mutations in exon 49 of the COL4A3 gene: c.4486C¡T (CGA¡TGA; p.Arg1496X) and c.4546C¡T (CGA¡TGA; p.Arg1516X; Fig 2). Her younger sister had the same heterozygous mutations in COL4A3. In both sisters, heterozygous polymorphisms were detected in exons 7, 9, and 38, along with homozygous polymorphisms in exons 21 and 25. Additional genetic testing of the parents showed that their father was heterozygous for the p.Arg1496X mutation and their mother was heterozygous for the p.Arg1516X mutation, confirming that these mutations were in trans. The family’s pedigree is shown in Fig 1. Subsequent to the initial presentation of these results,3 DNA mutations in these patients were reported online.4
Figure 1. Pedigree shows COL4A3 mutations.
inhibitor was initiated. One year after the initial diagnosis, serum creatinine level was 1.1 mg/dL (97 mol/L), and estimated creatinine clearance was 89 mL/min/1.73 m2 (1.48 mL/s). To confirm the diagnosis, ␣3(IV) and ␣4(IV) collagen genes were subjected to direct DNA sequencing (Mato Nagel, Weißwasser, Germany). Genomic DNA sequencing of the COL4A3 gene was performed by using dye terminators, and fragments were separated by using capillary electrophoresis on an ABI Prism 310 platform (Applied Biosystems, Foster City, CA).
DISCUSSION Two novel mutations in the COL4A3 gene were found in African American siblings with autosomal recessive Alport syndrome. They are compound heterozygotes, having inherited a deleterious mutation from each of their parents. Both siblings have symptomatic renal disease and significant hearing deficits. However, their parents, both carriers, are asymptomatic. Early development of chronic kidney failure in combination with deafness increasingly has been seen in the autosomal recessive form of Alport syn-
Figure 2. Schematic representation of the molecular organization of type IV collagen in the glomerular basement membrane (GBM). (A) The GBM, located between podocytes and endothelial cells, is formed by a suprastructure of type IV collagen that consists of protomers. (B) Each protomer, created by 3 ␣(IV) chains, has a 7S domain at the N-terminal, a long triple helical collagenous domain, and a noncollagenous (NC1) trimer at the C terminal. (C) Type IV collagen ␣3 chain. (D) The NC1 domain is composed of 2 homologous subdomains; the first is shown here. The highlighted defects at position 1496 and 1516 represent the nonsense mutations seen in our patients.
Novel Mutations in Alport Syndrome
drome, which accounts for only 15% of all forms. In many cases, autosomal recessive Alport syndrome is the result of consanguinity,4 although this was not the case in our family. Few case reports described African Americans with Alport syndrome; none were noted to be compound heterozygotes.5 There are approximately 30 different mutations resulting in autosomal recessive Alport syndrome, with the majority caused by COL4A4 mutations.6 Most cases report a missense mutation causing a glycine substitution, which interferes with normal folding of the triple helical protomers. These missense mutations are located primarily in the collagenous portion of the ␣3 or ␣4 collagen chains. Our nonsense mutations, p.Arg1496X and p.Arg1516X, were located in the noncollagenous (NC1) domain of the COL4A3 gene. An intact NC1 domain is necessary for formation of the collagenous triple helix needed for the ␣3␣4␣5 (IV) network that is essential in basement membrane structures. In our patients, replacement of the arginine residue (Arg) created premature stop codons (X), which presumptively lead to a truncated protein. Subsequently, the collagen chain was shortened by approximately 170 amino acids. Nonsense mutations are less common. However, Lemmink et al7,8 reported a case of a Norwegian brother and sister who were compound heterozygotes for nonsense mutations in the NC1 domain at the terminal end of the ␣3 collagen chain. There were other reported NC1 domain defects typically resulting from either deletions or splice-site mutations.8 Mutations in the NC1 domain seem to differ clinically from collagenous helix mutations with relation to degree of renal disease and severity and timing of hearing loss. Mutations at the terminal end of the gene creating an early truncation appear to cause kidney failure and sensorineural deafness at an early age, as seen in our patients. However, the missense mutations of glycines in the collagen helix cause deterioration in kidney function with only mild or late-onset deafness after the third decade.9,10 In our case, because the younger sibling had the same genotype as the index sibling, it is predicted that she also will develop the same early clinical features of Alport syndrome.
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There are 12 conserved cysteine residues located in the NC1 domain that have been considered crucial in linking type IV collagen molecules together to form basement membranes. Whether the conserved cysteine residues have a role in genotype-phenotype correlation is unknown. If there is a role, based on our 2 patients, we propose that an individual must have more than 4 intact cysteine residues to have a functioning collagen basement membrane network. However, additional subjects with premature chain terminations secondary to distal NC1 domain mutations are needed to further substantiate this theory. A few carriers with heterozygous mutations in COL4A3 were observed to progress to chronic kidney failure.11,12 However, there is a wide spectrum of phenotypes in which some carriers are completely asymptomatic, whereas others have persistent or intermittent microscopic hematuria.13 In our case, the father, who was found to carry the p.Arg1496X mutation, is an asymptomatic donor. He continues to have no evidence of hematuria or proteinuria since donor nephrectomy. Since transplantation, the older sister has shown stable kidney function without proteinuria or hematuria. There is limited information regarding the outcome of asymptomatic donors; hence, it is important to identify their carrier status with close follow-up after transplantation.14 In conclusion, we discovered 2 African American siblings with novel mutations of exon 49 on the COL4A3 gene resulting in Alport syndrome. They are both nonsense mutations in the NC1 domain of the ␣3(IV) collagen chain resulting in premature chain termination. The mechanism of mutations in the NC1 domain was reported in only 2 other families, neither African American.7,8 Of these 2 patients, only 1 was a compound heterozygote. Only in our patient was there a documented family history negative for consanguinity, which commonly accounts for autosomal recessive Alport syndrome. In an African American population in which autosomal recessive Alport syndrome is rarely seen, complete sequencing of the COL4A3 and COL4A4 genes may be necessary to identify the underlying mutation and confirm the diagnosis.
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Cook, Friedrich, and Baliga
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.
REFERENCES 1. Kashtan CE: Alport syndrome: Abnormalities of type IV collagen genes and proteins. Ren Fail 22:737-749, 2000 2. Kashtan CE: Collagen IV-Related Nephropathies (Alport Syndrome and Thin Basement Membrane Nephropathy). Gene Reviews. Available at: www.genetests.org. Accessed January 8, 2007 3. Barnett GL, Baliga R, Friedrich CA: Two previously unreported COL4A3 mutations in a patient with autosomal recessive Alport syndrome. Presented at the American Society of Human Genetics 55th Annual Meeting, Salt Lake City, UT, October 25-29, 2005 (abstr 2126) 4. Nagel M, Nagorka S, Gross O: Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum Mutat, Mutation in Brief #820 (2005) online. Available at: http://www3.interscience.wiley.com/homepages/38515/pdf/820. pdf. Accessed March 20, 2008 5. Schatz H: Alport’s syndrome in a Negro kindred. Am J Ophthalmol 71:1236-1240, 1971 6. Rana K, Tonna S, Wang YY, et al: Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases. Pediatr Nephrol 22:652-657, 2007
7. Lemmink HH, Mochizuki T, van den Heuvel LPWJ, et al: Mutations in the type IV␣3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3:1269-1273, 1994 8. Lemmink HH, Schroder CH, Monners LA, Smeets HJM: The clinical spectrum of type IV collagen mutations. Hum Mutat 9:477-499, 1997 9. Jais JP, Knebelmann B, Giatras I, et al: X-Linked Alport syndrome; Natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649-657, 2000 10. Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M: Meta-analysis of genotype-phenotype correlation in Xlinked Alport syndrome: Impact on clinical counseling. Nephrol Dial Transplant 17:1218-1227, 2002 11. Longo I, Scala E, Mari F, et al: Autosomal recessive Alport syndrome: An in-depth clinical and molecular analysis of five families. Nephrol Dial Transplant 21:665-671, 2006 12. Voskarides K, Damianou L, Neocleous V, et al: COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004-3016, 2007 13. Gubler MC: Inherited diseases of the glomerular basement membrane. Nat Clin Pract Nephrol 4:24-37, 2008 14. Kashtan CE: The wages of thin. J Am Soc Nephrol 18:2800-2802, 2007
A
lport syndrome is a progressive hereditary nephropathy often associated with extrarenal manifestations, including sensorineural deafness and/or ocular abnormalities.1 It is a genetically heterogeneous disease caused by mutations in type IV collagen of the basement membrane. Inheritance patterns include X-linked dominant (80%), autosomal recessive (15%), and autosomal dominant (5%).2 The autosomal recessive form is caused by mutations in either the COL4A3 or COL4A4 collagen genes. It rarely was reported in African Americans. We describe novel nonsense mutations in the COL4A3 gene in African American siblings who are compound heterozygotes for autosomal recessive Alport syndrome.
CASE REPORTS Patient 1 A 14-year-old African American girl presented with a 2-day history of headaches. Her review of systems was negative except for a 1-year history of progressive hearing loss. On examination, blood pressure was 168/119 mm Hg, with normal fundi and 1⫹ pitting edema of the lower extremities. Serum creatinine level was 4.3 mg/dL (380 mol/L), and blood urea nitrogen level was 30 mg/dL (10.7 mmol/L). Estimated creatinine clearance was 21 mL/min/ 1.73 m2 (0.35 mL/s). On urinalysis, there was 3⫹ protein and moderate blood. Urinary protein-creatinine ratio was 4.0 (normal, ⬍0.2). Twenty-four–hour urine protein excretion was 5.8 g. Serum total protein level was 7.3 g/dL (73 g/L), and albumin level was 3.9 g/dL (39 g/L). Serum cholesterol level was increased at 251 mg/dL (6.49 mmol/L). A renal biopsy specimen showed changes consistent with Alport syndrome. Audiometry confirmed the presence of moderate bilateral sensorineural hearing loss. A skin biopsy specimen showed uninterrupted staining of epidermal basement membrane for the ␣5 chain of type IV collagen (CE
Kashtan, Minneapolis, MN). The patient was started on calcium channel blocker therapy. Peritoneal dialysis therapy was initiated 5 months later. One year after her initial presentation, she received a living related donor kidney transplant from her father. Twenty-seven months after transplantation, both the donor and recipient have had no proteinuria or hematuria. Renal function of the recipient remains stable with a serum creatinine level of 1.4 mg/dL (124 mol/L), blood urea nitrogen level of 15 mg/dL (5 mmol/L), and urinary protein-creatinine ratio of 0.1.
Patient 2 The 11-year-old sister of patient 1 was evaluated for hematuria and a 2-month history of intermittent headaches. She had no known hearing deficit. Blood pressure was 133/80 mm Hg, and physical examination findings were unremarkable. Serum creatinine level was 0.7 mg/dL (62 mol/L), and blood urea nitrogen level was 7 mg/dL (2.5 mmol/L). Estimated creatinine clearance was 124 mL/min/ 1.73 m2 (2.07 mL/s). On urinalysis, there was 3⫹ protein and large blood. Twenty-four–hour urine protein excretion was 2.5 g. Total serum protein level was 5.0 g/dL (50 g/L), and albumin level was 3.4 g/dL (34 g/L). Serum cholesterol level was increased at 253 mg/dL (6.54 mmol/L). The renal biopsy specimen showed findings consistent with Alport syndrome. Audiometry showed bilateral sensorineural hearing loss. Treatment with an angiotensin-converting enzyme
From the 1Department of Pediatrics and 2Department of Preventive Medicine, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, MS. Received and accepted in revised form January 31, 2008. Originally published online as doi:10.1053/j.ajkd.2007.09.028 on April 2, 2008. Address correspondence to Radhakrishna Baliga, MD, Department of Pediatrics, 2500 North State St, Jackson, MS 39216. E-mail: [email protected] © 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5105-0001$34.00/0 doi:10.1053/j.ajkd.2007.09.028
American Journal of Kidney Diseases, Vol 51, No 5 (May), 2008: e25-e28
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Cook, Friedrich, and Baliga Direct DNA sequencing in the older sister indicated 2 heterozygous mutations in exon 49 of the COL4A3 gene: c.4486C¡T (CGA¡TGA; p.Arg1496X) and c.4546C¡T (CGA¡TGA; p.Arg1516X; Fig 2). Her younger sister had the same heterozygous mutations in COL4A3. In both sisters, heterozygous polymorphisms were detected in exons 7, 9, and 38, along with homozygous polymorphisms in exons 21 and 25. Additional genetic testing of the parents showed that their father was heterozygous for the p.Arg1496X mutation and their mother was heterozygous for the p.Arg1516X mutation, confirming that these mutations were in trans. The family’s pedigree is shown in Fig 1. Subsequent to the initial presentation of these results,3 DNA mutations in these patients were reported online.4
Figure 1. Pedigree shows COL4A3 mutations.
inhibitor was initiated. One year after the initial diagnosis, serum creatinine level was 1.1 mg/dL (97 mol/L), and estimated creatinine clearance was 89 mL/min/1.73 m2 (1.48 mL/s). To confirm the diagnosis, ␣3(IV) and ␣4(IV) collagen genes were subjected to direct DNA sequencing (Mato Nagel, Weißwasser, Germany). Genomic DNA sequencing of the COL4A3 gene was performed by using dye terminators, and fragments were separated by using capillary electrophoresis on an ABI Prism 310 platform (Applied Biosystems, Foster City, CA).
DISCUSSION Two novel mutations in the COL4A3 gene were found in African American siblings with autosomal recessive Alport syndrome. They are compound heterozygotes, having inherited a deleterious mutation from each of their parents. Both siblings have symptomatic renal disease and significant hearing deficits. However, their parents, both carriers, are asymptomatic. Early development of chronic kidney failure in combination with deafness increasingly has been seen in the autosomal recessive form of Alport syn-
Figure 2. Schematic representation of the molecular organization of type IV collagen in the glomerular basement membrane (GBM). (A) The GBM, located between podocytes and endothelial cells, is formed by a suprastructure of type IV collagen that consists of protomers. (B) Each protomer, created by 3 ␣(IV) chains, has a 7S domain at the N-terminal, a long triple helical collagenous domain, and a noncollagenous (NC1) trimer at the C terminal. (C) Type IV collagen ␣3 chain. (D) The NC1 domain is composed of 2 homologous subdomains; the first is shown here. The highlighted defects at position 1496 and 1516 represent the nonsense mutations seen in our patients.
Novel Mutations in Alport Syndrome
drome, which accounts for only 15% of all forms. In many cases, autosomal recessive Alport syndrome is the result of consanguinity,4 although this was not the case in our family. Few case reports described African Americans with Alport syndrome; none were noted to be compound heterozygotes.5 There are approximately 30 different mutations resulting in autosomal recessive Alport syndrome, with the majority caused by COL4A4 mutations.6 Most cases report a missense mutation causing a glycine substitution, which interferes with normal folding of the triple helical protomers. These missense mutations are located primarily in the collagenous portion of the ␣3 or ␣4 collagen chains. Our nonsense mutations, p.Arg1496X and p.Arg1516X, were located in the noncollagenous (NC1) domain of the COL4A3 gene. An intact NC1 domain is necessary for formation of the collagenous triple helix needed for the ␣3␣4␣5 (IV) network that is essential in basement membrane structures. In our patients, replacement of the arginine residue (Arg) created premature stop codons (X), which presumptively lead to a truncated protein. Subsequently, the collagen chain was shortened by approximately 170 amino acids. Nonsense mutations are less common. However, Lemmink et al7,8 reported a case of a Norwegian brother and sister who were compound heterozygotes for nonsense mutations in the NC1 domain at the terminal end of the ␣3 collagen chain. There were other reported NC1 domain defects typically resulting from either deletions or splice-site mutations.8 Mutations in the NC1 domain seem to differ clinically from collagenous helix mutations with relation to degree of renal disease and severity and timing of hearing loss. Mutations at the terminal end of the gene creating an early truncation appear to cause kidney failure and sensorineural deafness at an early age, as seen in our patients. However, the missense mutations of glycines in the collagen helix cause deterioration in kidney function with only mild or late-onset deafness after the third decade.9,10 In our case, because the younger sibling had the same genotype as the index sibling, it is predicted that she also will develop the same early clinical features of Alport syndrome.
e27
There are 12 conserved cysteine residues located in the NC1 domain that have been considered crucial in linking type IV collagen molecules together to form basement membranes. Whether the conserved cysteine residues have a role in genotype-phenotype correlation is unknown. If there is a role, based on our 2 patients, we propose that an individual must have more than 4 intact cysteine residues to have a functioning collagen basement membrane network. However, additional subjects with premature chain terminations secondary to distal NC1 domain mutations are needed to further substantiate this theory. A few carriers with heterozygous mutations in COL4A3 were observed to progress to chronic kidney failure.11,12 However, there is a wide spectrum of phenotypes in which some carriers are completely asymptomatic, whereas others have persistent or intermittent microscopic hematuria.13 In our case, the father, who was found to carry the p.Arg1496X mutation, is an asymptomatic donor. He continues to have no evidence of hematuria or proteinuria since donor nephrectomy. Since transplantation, the older sister has shown stable kidney function without proteinuria or hematuria. There is limited information regarding the outcome of asymptomatic donors; hence, it is important to identify their carrier status with close follow-up after transplantation.14 In conclusion, we discovered 2 African American siblings with novel mutations of exon 49 on the COL4A3 gene resulting in Alport syndrome. They are both nonsense mutations in the NC1 domain of the ␣3(IV) collagen chain resulting in premature chain termination. The mechanism of mutations in the NC1 domain was reported in only 2 other families, neither African American.7,8 Of these 2 patients, only 1 was a compound heterozygote. Only in our patient was there a documented family history negative for consanguinity, which commonly accounts for autosomal recessive Alport syndrome. In an African American population in which autosomal recessive Alport syndrome is rarely seen, complete sequencing of the COL4A3 and COL4A4 genes may be necessary to identify the underlying mutation and confirm the diagnosis.
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Cook, Friedrich, and Baliga
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None.
REFERENCES 1. Kashtan CE: Alport syndrome: Abnormalities of type IV collagen genes and proteins. Ren Fail 22:737-749, 2000 2. Kashtan CE: Collagen IV-Related Nephropathies (Alport Syndrome and Thin Basement Membrane Nephropathy). Gene Reviews. Available at: www.genetests.org. Accessed January 8, 2007 3. Barnett GL, Baliga R, Friedrich CA: Two previously unreported COL4A3 mutations in a patient with autosomal recessive Alport syndrome. Presented at the American Society of Human Genetics 55th Annual Meeting, Salt Lake City, UT, October 25-29, 2005 (abstr 2126) 4. Nagel M, Nagorka S, Gross O: Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Hum Mutat, Mutation in Brief #820 (2005) online. Available at: http://www3.interscience.wiley.com/homepages/38515/pdf/820. pdf. Accessed March 20, 2008 5. Schatz H: Alport’s syndrome in a Negro kindred. Am J Ophthalmol 71:1236-1240, 1971 6. Rana K, Tonna S, Wang YY, et al: Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases. Pediatr Nephrol 22:652-657, 2007
7. Lemmink HH, Mochizuki T, van den Heuvel LPWJ, et al: Mutations in the type IV␣3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3:1269-1273, 1994 8. Lemmink HH, Schroder CH, Monners LA, Smeets HJM: The clinical spectrum of type IV collagen mutations. Hum Mutat 9:477-499, 1997 9. Jais JP, Knebelmann B, Giatras I, et al: X-Linked Alport syndrome; Natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649-657, 2000 10. Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M: Meta-analysis of genotype-phenotype correlation in Xlinked Alport syndrome: Impact on clinical counseling. Nephrol Dial Transplant 17:1218-1227, 2002 11. Longo I, Scala E, Mari F, et al: Autosomal recessive Alport syndrome: An in-depth clinical and molecular analysis of five families. Nephrol Dial Transplant 21:665-671, 2006 12. Voskarides K, Damianou L, Neocleous V, et al: COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004-3016, 2007 13. Gubler MC: Inherited diseases of the glomerular basement membrane. Nat Clin Pract Nephrol 4:24-37, 2008 14. Kashtan CE: The wages of thin. J Am Soc Nephrol 18:2800-2802, 2007