Frameshift Mutation of the Zinc Finger Homeo Box 1 B Gene in Syndromic Corpus Callosum Agenesis (Mowat-Wilson Syndrome)

Abstract

We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations.

ZFHX1 B mutation - corpus callosum agenesis - microcephaly - mental retardation - Hirschsprung disease

References

• 1 Amiel J, Espinosa-Parrilla Y, Steffann J, Gosset P, Pelet A, Prieur M. et al . Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures.  Am J Hum Genet. 2001;  69 1370-1377
• 2 Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review.  J Med Genet. 2001;  38 729-739
• 3 Cacheux V, Moal F D, Kääriäinen H, Bondurand N, Rintala R, Boissier B. et al . Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.  Hum Mol Genet. 2001;  10 1503-1510
• 4 Dobyns W B. Absence makes the search grow longer.  Am J Hum Genet. 1996;  58 7-16
• 5 Espinosa-Parrilla Y, Amiel J, Auge J, Encha-Razavi F, Munnich A, Lyonnet S. et al . Expression of the SMADIP1 gene during early human development.  Mech Dev. 2002;  114 187-191
• 6 Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I. et al . Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis.  Eur J Hum Genet. 2001;  9 561-571
• 7 Heldin C H, Miyazono K, ten Dijke P. TGF-β signaling from cell membrane to nucleus through SMAD proteins.  Nature. 1997;  390 465-471
• 8 Mowat D R, Croaker G DH, Cass D T, Kerr B A, Chaitow J, Adės L C. et al . Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2 q22-q23.  J Med Genet. 1998;  35 617-623
• 9 Remacle J E, Kraft H, Lerchner W, Wuytens G, Collart C, Verschueren K. et al . New mode of DNA binding of multi-zinc finger transcription factors: δEF1 family members bind with two hands to two target sites.  EMBO J. 1999;  18 5073-5084
• 10 Verschueren K, Remacle J E, Collart C, Kraft H, Baker B S, Tylzanowski P. et al . SIP1, a novel zinc finger/homeodomain repressor, interacts with smad proteins and binds to 5′CACCT sequences in candidate target genes.  J Biol Chem. 1999;  274 20489-20498
• 11 Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H. et al . Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease.  Nature Genet. 2001;  27 369-370
• 12 Yamada K, Yamada Y, Nomura N, Miura K, Wakako R, Hayakawa C. et al . Nonsense and frameshift mutations in ZFHX1 B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features.  Am J Hum Genet. 2001;  69 1178-1185
• 13 Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G. et al . “Mowat-Wilson” syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies mental retardation syndrome caused by mutations in the zinc finger homeo box 1 B gene.  Am J Med Genet. 2002;  108 177-181