Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway

Abstract

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.

Figure 1.

Israeli-Bedouin kindreds affected with LCCS2. Blackened and unblackened symbols represent affected and unaffected individuals, respectively. The numbers denote individuals whose DNA samples were analyzed. A, Pedigree of family A. B, Pedigree of family B.

Figure 2.

Linkage results for chromosome 12 of two nuclear families of family A. The haplotype showing the homozygosity region is boxed. The arrow indicates a crossing-over event. The lower boundary was determined on the basis of analysis of individual 61.

Figure 3.

Sequence analysis of the ERBB3 gene in an LCCS2-affected individual. A, Homozygosity for the G→A substitution in intron 10 (affected individual 61). B, Insertion (8 bp) in the cDNA sequence at position 1183 of the ERBB3 gene. chr = Chromosome; ex = exon. C, Schematic representation of the chromosomal locus, the genomic DNA of ERBB3, and the IVS10-8A→G mutation. D, The splice variation occurring in affected individuals. E, Schematic illustration of the protein structure of ErbB3 (according to InterPro) and the predicted mutant truncated protein (395FS399Stop). RLD = Recep_L_domain; FU = Furin-like domain.

Figure 4.

Splice-site prediction with use of the Neural Networks Splice Site Prediction software (Berkeley Drosophila Genome Project). An alternative additional acceptor splice site was predicted for the ERBB3-mutated sequence.