Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway.
Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. We previously mapped LCCS2 to 6.4 Mb on chromosome 12q13 and have now narrowed the locus to 4.6 Mb. We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein. ERBB3 (Her3), an activator of the phosphatidylinositol-3-kinase/Akt pathway--regulating cell survival and vesicle trafficking--is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons. Gain-of-function mutations in members of the epidermal growth-factor tyrosine kinase-receptor family have been associated with predilection to cancer. This is the first report of a human phenotype resulting from loss of function of a member of this group.
Narkis
Ginat
G
Morris Kahn Laboratory of Human Genetics, National Institute of Biotechnology in Negev, Beer-Sheva, Israel.
Ofir
Rivka
R
Manor
Esther
E
Landau
Daniella
D
Elbedour
Khalil
K
Birk
Ohad S
OS
D017398:Alternative Splicing; D001176:Arthrogryposis / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics*; D013577:Syndrome
D019869:Phosphatidylinositol 3-Kinases; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt
Cytogenet Cell Genet. 2000;89(1-2):92-5
10894945
J Biol Chem. 1995 Feb 17;270(7):2881-4
7852364
Annu Rev Biochem. 2001;70:535-602
11395417
Science. 2002 Aug 23;297(5585):1330-3
12154198
Am J Med Genet A. 2003 Feb 15;117A(1):37-40
12548738
J Biol Chem. 2003 Sep 12;278(37):35702-9
12824184
J Membr Biol. 2003 Jul 15;194(2):77-89
14502432
Nat Genet. 2004 Apr;36(4):400-4
15052268
J Biol Chem. 1996 Dec 20;271(51):32937-43
8955136
FEBS Lett. 1997 Jun 23;410(1):83-6
9247128
Nature. 1997 Oct 16;389(6652):725-30
9338783
Biochem J. 1998 Aug 1;333 ( Pt 3):757-63
9677338
Biochem J. 2005 Sep 1;390(Pt 2):613-23
15913452
Trends Pharmacol Sci. 2005 Dec;26(12):654-60
16253350
Blood. 2005 Dec 15;106(13):4159-66
16123220
Am J Hum Genet. 2007 Sep;81(3):530-9
17701898
Am J Med Genet A. 2004 Oct 15;130A(3):272-6
15378541
Cancer Res. 2001 Jun 1;61(11):4467-73
11389077