Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum

Verena Matejas (1) , Bernward Hinkes (2, 3) , Faisal Alkandari (4) , Lihadh Al-Gazali (5) , Ellen Annexstad (6) , Mehmet Aytac (7) , Margaret Barrow (8) , Kveta Blahova (9) , Detlef Bockenhauer (10) , Hae Il Cheong (11) , Iwona Maruniak-Chudek (12) , Pierre Cochat (13) , Priya Gajjar (14) , Raoul Hennekam (15) , Francoise Janssen (16) , Mikhail Kagan (17) , Ariana Kariminejad (18) , Markus Kemper (19) , Jens Koenig (20) , Jillene Kogan (21) , Yolande H Kroes , Eberhard Kuwertz-Bröking (20) , Amy Lewanda (22) , Ana Medeira (23) , Jutta Muscheites (24) , Patrick Niaudet (25) , Michel Pierson (26) , Anand Saggar (27) , Laurie Seaver (28) , Mohnish Suri (29) , Alexey Tsygin (30) , Elke Wuehl (31) , Aleksandra Zurowska (32) , Steffen Uebe (1) , Friedhelm Hildebrandt (33) , Corinne Antignac (34) , Martin Zenker (35)

1 Institute of Human Genetics [Erlangen, Allemagne]
2 Pediatric Nephrology
3 Howard Hughes Medical Institute and Departments of Pediatrics and Human Genetics
4 Pediatric Department
5 Department of Pediatrics
6 Oslo University Hospital [Oslo]
7 Department of Pediatric Nephrology
8 Leicester Royal Infirmary
9 Department of Pediatrics
10 Pediatric Nephrology
11 Dept. of Pediatrics
12 Department of Neonatal Intensive Care
13 Département de Pédiatrie
14 Paediatric Nephrology, Dept. of Paediatric Medicine
15 Dept. of Clinical Genetics
16 Department of Pediatric Nephrology
17 Department of Gastroenterology and Nephrology
18 Kariminejad-Najmabadi Pathology& Genetics Center
19 Pediatric Nephrology
20 University Children's Hospital, Munster
21 Department of Human Genetics
22 Inova Fairfax Hospital for Children
23 Hospital Santa Maria
24 Pediatric Nephrology
25 Service de néphrologie pédiatrique [CHU Necker]
26 University Children's Hospital Nancy
27 St. George's University of London
28 Kapiolani Medical Specialists and Department of [e-mail]
29 Clinical Genetics Service
30 Nephrology
31 Pediatric Nephrology
32 Department Pediatric & Adolescent Nephrology & Hypertension
33 Pediatrics
34 Hôpital Necker - Enfants Malades [AP-HP]
35 Institute of Human Genetics

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Mots clés: Life Sciences

Verena Matejas, Bernward Hinkes, Faisal Alkandari, Lihadh Al-Gazali, Ellen Annexstad, et al.. Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum. Human Mutation, 2010, 31 (9), pp.992. ⟨10.1002/humu.21304⟩. ⟨hal-00555316⟩