PMID- 10556296
OWN - NLM
STAT- MEDLINE
DCOM- 20000124
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 13
DP  - 1999 Dec
TI  - The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH
      mutations cause a significant proportion of autosomal dominant holoprosencephaly.
PG  - 2479-88
AB  - Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain 
      and midface where the cerebral hemispheres fail to separate into distinct left
      and right halves. We have previously reported haploinsufficiency for Sonic
      Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of
      the complete coding region and intron-exon junctions of the SHH gene in 344
      unrelated affected individuals. Herein, we describe 13 additional unrelated
      affected individuals with SHH mutations, including nonsense and missense
      mutations, deletions and an insertion. These mutations occur throughout the
      extent of the gene. No specific genotype-phenotype association is evident based
      on the correlation of the type or position of the mutations. In conjunction with 
      our previous studies, we have identified a total of 23 mutations in 344 unrelated
      cases of HPE. They account for 14 cases of familial HPE and nine cases of
      sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing
      autosomal dominant transmission of the HPE spectrum, based on structural
      anomalies. Interestingly, three of the patients with an SHH mutation also had
      abnormalities in another gene that is expressed during forebrain development. We 
      suggest that the interactions of multiple gene products and/or environmental
      elements may determine the final phenotypic outcome for a given individual and
      that variations among these factors may cause the wide variability in the
      clinical features seen in HPE.
FAU - Nanni, L
AU  - Nanni L
AD  - Departments of Pediatrics and Genetics, The Children's Hospital of Philadelphia, 
      University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4399, USA.
FAU - Ming, J E
AU  - Ming JE
FAU - Bocian, M
AU  - Bocian M
FAU - Steinhaus, K
AU  - Steinhaus K
FAU - Bianchi, D W
AU  - Bianchi DW
FAU - Die-Smulders, C
AU  - Die-Smulders C
FAU - Giannotti, A
AU  - Giannotti A
FAU - Imaizumi, K
AU  - Imaizumi K
FAU - Jones, K L
AU  - Jones KL
FAU - Campo, M D
AU  - Campo MD
FAU - Martin, R A
AU  - Martin RA
FAU - Meinecke, P
AU  - Meinecke P
FAU - Pierpont, M E
AU  - Pierpont ME
FAU - Robin, N H
AU  - Robin NH
FAU - Young, I D
AU  - Young ID
FAU - Roessler, E
AU  - Roessler E
FAU - Muenke, M
AU  - Muenke M
LA  - eng
GR  - HD01218/HD/NICHD NIH HHS/United States
GR  - HD28732/HD/NICHD NIH HHS/United States
GR  - HD29862/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Proteins)
RN  - 0 (SHH protein, human)
RN  - 0 (Trans-Activators)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Amino Acid Sequence
MH  - DNA/*analysis
MH  - DNA Mutational Analysis
MH  - Frameshift Mutation
MH  - Hedgehog Proteins
MH  - Holoprosencephaly/*genetics/metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Mutagenesis, Insertional
MH  - Mutation, Missense
MH  - Pedigree
MH  - Phenotype
MH  - Polymorphism, Single-Stranded Conformational
MH  - Proteins/*genetics/metabolism
MH  - Sequence Alignment
MH  - *Trans-Activators
EDAT- 1999/11/11 00:00
MHDA- 1999/11/11 00:01
CRDT- 1999/11/11 00:00
PHST- 1999/11/11 00:00 [pubmed]
PHST- 1999/11/11 00:01 [medline]
PHST- 1999/11/11 00:00 [entrez]
AID - ddc285 [pii]
AID - 10.1093/hmg/8.13.2479 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Dec;8(13):2479-88. doi: 10.1093/hmg/8.13.2479.