Advertisement

Human Genetics

, Volume 120, Issue 2, pp 211–226 | Cite as

Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity

  • Erica R. Eichers
  • Muhammad M. Abd-El-Barr
  • Richard Paylor
  • Richard Alan Lewis
  • Weimin Bi
  • Xiaodi Lin
  • Thomas P. Meehan
  • David W. Stockton
  • Samuel M. Wu
  • Elizabeth Lindsay
  • Monica J. Justice
  • Philip L. Beales
  • Nicholas Katsanis
  • James R. Lupski
Original Investigation

Abstract

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20–30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.

Keywords

Null Mouse Neural Tube Defect Social Dominance Acoustic Startle Response Planar Cell Polarity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Isabel Lorenzo from the Darwin Transgenic Mouse Core Facility at Baylor College of Medicine for blastocyst injections and chimera production. At the Comparative Pathology Laboratory at Baylor College of Medicine we recognize Dr. Roger E. Price, Roxane Walden, and Vida Hortenstein for their aid with pathology, histology, and serum chemistry analysis, respectively. Additionally, we appreciate the statistical assistance of E. O’Brien Smith. ERE was supported in part by a National Science Foundation Graduate Teaching in Education Fellowship funded by grant number DGE-0086397. This work was also supported by the Baylor College of Medicine MRRDDRC Neurobehavioral and Administrative Core Facilities, a March of Dimes grant to NK and JRL, and Public Health Service grant U01 HD 39372 to MJJ. RAL is a Senior Scientific Investigator of Research to Prevent Blindness, New York. SMW would like to acknowledge the following funding sources: NIH EY0446 and EY02520, Retina Research Foundation (Houston), and International Retina Research Foundation Inc. PLB is a Wellcome Trust Senior Research Fellow. This research was also funded by grants R01 HD42601, R01 DK072301, and R01 EY016859 to NK.

Supplementary material

References

  1. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628–633PubMedCrossRefGoogle Scholar
  2. Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N (2003a) Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72:650–658CrossRefGoogle Scholar
  3. Badano JL, Kim JC, Hoskins BE, Lewis RA, Ansley SJ, Cutler DJ, Castellan C, Beales PL, Leroux MR, Katsanis N (2003b) Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet 12:1651–1659CrossRefGoogle Scholar
  4. Badano JL, Leitch CC, Ansley SJ, May-Simera H, Lawson S, Lewis RA, Beales PL, Dietz HC, Fisher S, Katsanis N (2006) Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 439:326–330PubMedCrossRefGoogle Scholar
  5. Barnett S, Reilly S, Carr L, Ojo I, Beales PL, Charman T (2002) Behavioural phenotype of Bardet-Biedl syndrome. J Med Genet 39:e76PubMedCrossRefGoogle Scholar
  6. Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, Mein CA, Froguel P, Scambler PJ, Lewis RA, Lupski JR, Katsanis N (2003) Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet 72:1187–1199PubMedCrossRefGoogle Scholar
  7. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA (1999) New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36:437–446PubMedGoogle Scholar
  8. Berson EL, Gouras P, Gunkel RD (1968) Progressive cone-rod degeneration. Arch Ophthalmol 80:68–76PubMedGoogle Scholar
  9. Bouwknecht JA, Paylor R (2002) Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav Brain Res 136:489–501PubMedCrossRefGoogle Scholar
  10. Bramblett DE, Pennesi ME, Wu SM, Tsai M-J (2004) The transcription factor Bhlhb4 is required for rod bipolar cell maturation. Neuron 43:779–793PubMedCrossRefGoogle Scholar
  11. Chiang AP, Beck JS, Yen H-J, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA, Kim K-YA, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, Sheffield VC (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 103:6287–6292PubMedCrossRefGoogle Scholar
  12. Chiang AP, Nishimura D, Searby C, Elbedour K, Carmi R, Ferguson AL, Secrist J, Braun T, Casavant T, Stone EM, Sheffield VC (2004) Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 75:475–484PubMedCrossRefGoogle Scholar
  13. Cooper AJ, Cowley JJ (1976) The effect of litter size on the growth, survival and behaviour of neonatal bulbectomised mice. Biol Neonate 29:56–65PubMedCrossRefGoogle Scholar
  14. Coppola DM, Coltrane JA, Arsov I (1994) Retronasal or internasal olfaction can mediate odor-guided behaviors in newborn mice. Physiol Behav 56:729–736PubMedCrossRefGoogle Scholar
  15. Craigen WJ (2001) Mouse models of human genetic disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, vol I. McGraw-Hill, New York, pp 379–415Google Scholar
  16. Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31:197–211PubMedCrossRefGoogle Scholar
  17. David A, Bitoun P, Lacombe D, Lambert J-C, Nivelon A, Vigneron J, Verloes A (1999) Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick–Kaufman syndromes. J Med Genet 36:599–603PubMedGoogle Scholar
  18. Dekaban AS (1969) Familial occurrence of congenital retinal blindness and developmental renal lesions. J Genet Hum 17:289–296PubMedGoogle Scholar
  19. Delaney V, Mullaney J, Bourke E (1978) Juvenile nephronophthisis, congenital hepatic fibrosis and retinal hypoplasia in twins. Q J Med XLVII:281–290Google Scholar
  20. Edwards DA, Thompson ML, Burge KG (1972) Olfactory bulb removal vs peripherally induced anosmia: differential effects on the aggressive behavior of male mice. Behav Biol 7:823–828PubMedCrossRefGoogle Scholar
  21. Eichers ER, Lewis RA, Katsanis N, Lupski JR (2004) Triallelic inheritance: a bridge between Mendelian and multifactorial traits. Ann Med 36:262–272PubMedCrossRefGoogle Scholar
  22. Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 36:989–993PubMedCrossRefGoogle Scholar
  23. Fath MA, Mullins RF, Searby C, Nishimura DY, Wei J, Rahmouni K, Davis RE, Tayeh MK, Andrews M, Yang B, Sigmund CD, Stone EM, Sheffield VC (2005) Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum Mol Genet 14:1109–1118PubMedCrossRefGoogle Scholar
  24. Franks PW, Brage S, Luan J, Ekelund U, Rahman M, Farooqi IS, Halsall I, O’Rahilly S, Wareham NJ (2005) Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obes Res 13:1476–1484PubMedCrossRefGoogle Scholar
  25. Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, Heath O, McManamon PJ, O’Leary E, Pryse-Phillips W (1989) The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 321:1002–1009PubMedCrossRefGoogle Scholar
  26. Héon E, Westall C, Carmi R, Elbedour K, Panton C, MacKeen L, Stone EM, Sheffield VC (2005) Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. Am J Med Genet 132A:283–287CrossRefPubMedGoogle Scholar
  27. Hongo T, Hakuba A, Shiota K, Naruse I (2000) Suckling dysfunction caused by defects in the olfactory system in genetic arhinencephaly mice. Biol Neonate 78:293–299PubMedCrossRefGoogle Scholar
  28. Hood DC, Birch DG (1996) b wave of the scotopic (rod) electroretinogram as a measure of the activity of human on-bipolar cells. J Opt Soc Am A 13:623–633CrossRefGoogle Scholar
  29. Iannello S, Bosco P, Cavaleri A, Camuto M, Milazzo P, Belfiore F (2002) A review of the literature of Bardet-Biedl disease and report of three cases associated with metabolic syndrome and diagnosed after the age of fifty. Obes Rev 3:123–135PubMedCrossRefGoogle Scholar
  30. Jacobson SG, Borruat F-X, Apáthy PP (1990) Patterns of rod and cone dysfunction in Bardet-Biedl syndrome. Am J Ophthalmol 109:676–688PubMedGoogle Scholar
  31. Jawień J, Nastałek P, Korbut R (2004) Mouse models of experimental atherosclerosis. J Physiol Pharmacol 55:503–517PubMedGoogle Scholar
  32. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001) Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293:2256–2259PubMedCrossRefGoogle Scholar
  33. Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson WS, Lupski JR (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet 26:67–70PubMedCrossRefGoogle Scholar
  34. Katsanis N, Eichers ER, Ansley SJ, Lewis RA, Kayserili H, Hoskins BE, Scambler PJ, Beales PL, Lupski JR (2002) BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance. Am J Hum Genet 71:22–29PubMedCrossRefGoogle Scholar
  35. Kim JC, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, Leitch CC, Venner K, Ansley SJ, Ross AJ, Leroux MR, Katsanis N, Beales PL (2004) The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36:462–470PubMedCrossRefGoogle Scholar
  36. Kulaga HM, Leitch CC, Eichers ER, Badano JL, Lesemann A, Hoskins BE, Lupski JR, Beales PL, Reed RR, Katsanis N (2004) Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat Genet 36:994–998PubMedCrossRefGoogle Scholar
  37. Lavy T, Harris CM, Shawkat F, Thompson D, Taylor D, Kriss A (1995) Electrophysiological and eye-movement abnormalities in children with the Bardet-Biedl syndrome. J Pediatr Ophthalmol Strabismus 32:364–367PubMedGoogle Scholar
  38. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117:541–552PubMedCrossRefGoogle Scholar
  39. Liebenauer LL, Slotnick BM (1996) Social organization and aggression in a group of olfactory bulbectomized male mice. Physiol Behav 60:403–409PubMedCrossRefGoogle Scholar
  40. McIlwain KL, Merriweather MY, Yuva-Paylor LA, Paylor R (2001) The use of behavioral test batteries: effects of training history. Physiol Behav 73:705–717PubMedCrossRefGoogle Scholar
  41. McKusick VA, Bauer RL, Koop CE, Scott RB (1964) Hydrometrocolpos as a simply inherited malformation. JAMA 189:813–816PubMedGoogle Scholar
  42. Meeker WR Jr, Nighbert EJ (1971) Association of cystic dilatation of intrahepatic and common bile ducts with Laurence-Moon-Biedl-Bardet syndrome. Am J Surg 122:822–824PubMedCrossRefGoogle Scholar
  43. Mehrotra N, Taub S, Covert RF (1997) Hydrometrocolpos as a neonatal manifestation of the Bardet-Biedl syndrome. Am J Med Genet 69:220PubMedCrossRefGoogle Scholar
  44. Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, Beck G, Wright AF, Iannaccone A, Elbedour K, Riise R, Baldi A, Raas-Rothschild A, Gorman SW, Duhl DM, Jacobson SG, Casavant T, Stone EM, Sheffield VC (2001) Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28:188–191PubMedCrossRefGoogle Scholar
  45. Mykytyn K, Mullins RF, Andrews M, Chiang AP, Swiderski RE, Yang B, Braun T, Casavant T, Stone EM, Sheffield VC (2004) Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc Natl Acad Sci USA 101:8664–8669PubMedCrossRefGoogle Scholar
  46. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen H-j, Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton AB, Carmi R, Lüleci G, Chandrasekharappa SC, Collins FS, Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, Sheffield VC (2002) Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31:435–438PubMedGoogle Scholar
  47. Nishimura DY, Fath M, Mullins RF, Searby C, Andrews M, Davis R, Andorf JL, Mykytyn K, Swiderski RE, Yang B, Carmi R, Stone EM, Sheffield VC (2004) Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci USA 101:16588–16593PubMedCrossRefGoogle Scholar
  48. Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, Lam BL, Powell BR, Swiderski RE, Bugge KE, Haider NB, Kwitek-Black AE, Ying L, Duhl DM, Gorman SW, Heon E, Iannaccone A, Bonneau D, Biesecker LG, Jacobson SG, Stone EM, Sheffield VC (2001) Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet 10:865–874PubMedCrossRefGoogle Scholar
  49. Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, Merin S, Weleber RG, Biesecker LG, Stone EM, Sheffield VC (2005) Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet 77:1021–1033PubMedCrossRefGoogle Scholar
  50. Pagon RA, Haas JE, Bunt AH, Rodaway KA (1982) Hepatic involvement in the Bardet-Biedl syndrome. Am J Med Genet 13:373–381PubMedCrossRefGoogle Scholar
  51. Paylor R, Spencer CM, Yuva-Paylor LA, Pieke-Dahl S (2006) The use of behavioral test batteries, II: effect of test interval. Physiol Behav 87:95–102PubMedCrossRefGoogle Scholar
  52. Pennesi ME, Howes KA, Baehr W, Wu SM (2003) Guanylate cyclase-activating protein (GCAP) 1 rescues cone recovery kinetics in GCAP1/GCAP2 knockout mice. Proc Natl Acad Sci USA 100:6783–6788PubMedCrossRefGoogle Scholar
  53. Pepperberg DR, Birch DG, Hood DC (1997) Photoresponses of human rods in vivo derived from paired-flash electroretinograms. Vis Neurosci 14:73–82PubMedCrossRefGoogle Scholar
  54. Proesmans W, Van Damme B, Macken J (1975) Nephronophthisis and tapetoretinal degeneration associated with liver fibrosis. Clin Nephrol 3:160–164PubMedGoogle Scholar
  55. Riise R, Andréasson S, Tornqvist K (1996a) Full-field electroretinograms in individuals with the Laurence-Moon-Bardet-Biedl syndrome. Acta Ophthalmol Scand 74:618–620Google Scholar
  56. Riise R, Andréasson S, Wright AF, Tornqvist K (1996b) Ocular findings in the Laurence-Moon-Bardet-Biedl syndrome. Acta Ophthalmol Scand 74:612–617CrossRefGoogle Scholar
  57. Rizzo JF III, Berson EL, Lessell S (1986) Retinal and neurologic findings in the Laurence-Moon-Bardet-Biedl phenotype. Ophthalmology 93:1452–1456PubMedGoogle Scholar
  58. Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot M-M, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL (2005) Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37:1135–1140PubMedCrossRefGoogle Scholar
  59. Ross CF, Crome L, Mackenzie DY (1956) The Laurence-Moon-Biedl syndrome. J Pathol Bacteriol LXXII:161–172CrossRefGoogle Scholar
  60. Schaap C, ten Tusscher MPM, Schrander JJP, Kuijten RH, Schrander-Stumpel CTRM (1998) Phenotypic overlap between McKusick–Kaufman and Bardet-Biedl syndromes: are they related? Eur J Pediatr 157:170–171PubMedGoogle Scholar
  61. Shawkat FS, Harris CM, Taylor DSI, Kriss A (1996) The role of ERG/VEP and eye movement recordings in children with ocular motor apraxia. Eye 10:53–60PubMedGoogle Scholar
  62. Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, Musarella MA, Parfrey PS, Sheffield VC, Biesecker LG (2000) Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet 26:15–16PubMedCrossRefGoogle Scholar
  63. Spencer CM, Alekseyenko O, Serysheva E, Yuva-Paylor LA, Paylor R (2005) Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav 4:420–430PubMedCrossRefGoogle Scholar
  64. Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, Leitch CC, Salem N, Chouery E, Corbani S, Jalk N, Vicaire S, Sarda P, Hamel C, Lacombe D, Holder M, Odent S, Holder S, Brooks AS, Elcioglu NH, Da Silva E, Rossillion B, Sigaudy S, de Ravel TJL, Lewis RA, Leheup B, Verloes A, Amati-Bonneau P, Mégarbané A, Poch O, Bonneau D, Beales PL, Mandel J-L, Katsanis N, Dollfus H (2006) BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38:521–524PubMedCrossRefGoogle Scholar
  65. Stoler JM, Herrin JT, Holmes LB (1995) Genital abnormalities in females with Bardet-Biedl syndrome. Am J Med Genet 55:276–278PubMedCrossRefGoogle Scholar
  66. Stone DL, Slavotinek A, Bouffard GG, Banerjee-Basu S, Baxevanis AD, Barr M, Biesecker LG (2000) Mutation of a gene encoding a putative chaperonin causes McKusick–Kaufman syndrome. Nat Genet 25:79–82PubMedCrossRefGoogle Scholar
  67. Teicher MH, Flaum LE, Williams M, Eckhert SJ, Lumia AR (1978) Survival, growth and suckling behavior of neonatally bulbectomized rats. Physiol Behav 21:553–561PubMedCrossRefGoogle Scholar
  68. Tsuchiya R, Nishimura R, Ito T (1977) Congenital cystic dilation of the bile duct associated with Laurence-Moon-Biedl-Bardet syndrome. Arch Surg 112:82–84PubMedGoogle Scholar
  69. Walz K, Spencer C, Kaasik K, Lee CC, Lupski JR, Paylor R (2004) Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2). Hum Mol Genet 13:367–378PubMedCrossRefGoogle Scholar
  70. Zimmet P, Boyko EJ, Collier GR, de Courten M (1999) Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players. Ann N Y Acad Sci 892:25–44PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Erica R. Eichers
    • 1
  • Muhammad M. Abd-El-Barr
    • 2
    • 3
  • Richard Paylor
    • 1
    • 2
  • Richard Alan Lewis
    • 1
    • 3
    • 4
    • 5
  • Weimin Bi
    • 1
  • Xiaodi Lin
    • 1
  • Thomas P. Meehan
    • 1
  • David W. Stockton
    • 1
    • 3
    • 5
    • 7
  • Samuel M. Wu
    • 2
    • 3
  • Elizabeth Lindsay
    • 6
  • Monica J. Justice
    • 1
  • Philip L. Beales
    • 8
  • Nicholas Katsanis
    • 9
    • 10
  • James R. Lupski
    • 1
    • 4
    • 7
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of NeuroscienceBaylor College of MedicineHoustonUSA
  3. 3.Department of OphthalmologyBaylor College of MedicineHoustonUSA
  4. 4.Department of PediatricsBaylor College of MedicineHoustonUSA
  5. 5.Department of MedicineBaylor College of MedicineHoustonUSA
  6. 6.Department of Pediatrics (Cardiology)Baylor College of Medicine HoustonUSA
  7. 7.Texas Children’s HospitalHoustonUSA
  8. 8.Molecular Medicine Unit, Institute of Child HealthUniversity College LondonLondonUK
  9. 9.McKusick-Nathans Institute of Genetic MedicineJohns Hopkins UniversityBaltimoreUSA
  10. 10.Wilmer Eye InstituteJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations