PMID- 10084596
OWN - NLM
STAT- MEDLINE
DCOM- 19990413
LR  - 20211203
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 84
IP  - 3
DP  - 1999 Mar
TI  - Two different mutations in the thyroid peroxidase gene of a large inbred Amish
      kindred: power and limits of homozygosity mapping.
PG  - 1061-71
AB  - Approximately 10% of newborns with congenital hypothyroidism are unable to
      convert iodide into organic iodine. This iodide organification defect has a
      prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid
      peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO
      substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of 
      severe hypothyroidism due to a complete iodide organification defect in the
      youngest generation of five nuclear families belonging to an inbred Amish
      kindred. Genealogical records permitted us to trace their origin to an ancestral 
      couple 7-8 generations back and to identify an autosomal recessive pattern of
      inheritance. Initial studies of homozygosity by descent using two polymorphic
      markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 
      affected siblings from 2 of the nuclear families were heterozygous, resulting in 
      homozygosity values of 73% and 53% in affected and unaffected family members,
      respectively. A genome-wide homozygosity screen using DNA pools from affected and
      unaffected family members localized the defect to a locus close to the TPO gene. 
      Linkage analysis using 4 additional polymorphic markers within the TPO gene
      reduced the number of homozygous unaffected siblings to zero without altering the
      percent homozygosity initially found in the affected. Sequencing of the TPO gene 
      revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both
      alleles of the 11 affected homozygotes, both mutations were present in each of
      the 3 affected compound heterozygotes, and there were no TPO mutations in 1
      subject with hypothyroidism of different etiology. These results demonstrate the 
      power of the DNA pooling strategy in the localization of a defective gene and the
      pitfalls of linkage analysis when 2 relatively rare mutations coexist in an
      inbred population.
FAU - Pannain, S
AU  - Pannain S
AD  - Department of Medicine, University of Chicago, Illinois 60637, USA.
FAU - Weiss, R E
AU  - Weiss RE
FAU - Jackson, C E
AU  - Jackson CE
FAU - Dian, D
AU  - Dian D
FAU - Beck, J C
AU  - Beck JC
FAU - Sheffield, V C
AU  - Sheffield VC
FAU - Cox, N
AU  - Cox N
FAU - Refetoff, S
AU  - Refetoff S
LA  - eng
GR  - DK-15070/DK/NIDDK NIH HHS/United States
GR  - HG-00497/HG/NHGRI NIH HHS/United States
GR  - RR-0050/RR/NCRR 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  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - EC 1.11.1.8 (Iodide Peroxidase)
SB  - IM
MH  - Child, Preschool
MH  - *Christianity
MH  - Chromosome Mapping
MH  - Congenital Hypothyroidism
MH  - *Consanguinity
MH  - *Ethnicity
MH  - Female
MH  - Genetic Linkage
MH  - Goiter/genetics
MH  - Haplotypes
MH  - Homozygote
MH  - Humans
MH  - Hypothyroidism/genetics
MH  - Intellectual Disability/genetics
MH  - Iodide Peroxidase/*genetics
MH  - Male
MH  - Mutation/*genetics
MH  - Pedigree
MH  - Phenotype
EDAT- 1999/03/20 00:00
MHDA- 1999/03/20 00:01
CRDT- 1999/03/20 00:00
PHST- 1999/03/20 00:00 [pubmed]
PHST- 1999/03/20 00:01 [medline]
PHST- 1999/03/20 00:00 [entrez]
AID - 10.1210/jcem.84.3.5541 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 1999 Mar;84(3):1061-71. doi: 10.1210/jcem.84.3.5541.