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Endocrine Abstracts (2018) 57 007 | DOI: 10.1530/endoabs.57.007

BES2018 BES 2018 A heterozygous splice-site mutation in PTHLH causes autosomal dominant shorting of metacarpals and -tarsals (1 abstracts)

A heterozygous splice-site mutation in PTHLH causes autosomal dominant shorting of metacarpals and -tarsals

Reyes Monica 1 , Bravenboer Bert 2 & Jüppner Harald 1


1Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; 2Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium.

Short metacarpals and/or -tarsals are observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP) caused by inactivating GNAS mutations involving exons encoding the stimulatory G protein alpha-subunit (Gαs). Skeletal abnormalities indistinguishable from those caused by Gαs mutations were present in five members of an extended Belgian family, who showed no evidence for abnormal regulation of calcium and phosphate homeostasis. Direct nucleotide sequencing of the proband’s (190/II-1) genomic DNA excluded mutations involving GNAS exons 1-13, but whole exome analysis revealed a heterozygous A>G change at nucleotide -3 of PTHLH exon 3 that encodes the last two amino acids of the Pre-Pro sequence of PTHrP. The same nucleotide change was also found in the proband’s affected sister 190/II-2 and three of this sister’s descendants (190/III-1, 190/IV-1, and 190/IV-2), but not in two unaffected family members and not in public databases. Complementary DNA derived from immortalized lymphoblastoid cells of the affected male 190/IV-2 and his unaffected sister 190/IV-3 was PCR-amplified using forward primers located either in PTHLH exon 1 or 2, and reverse primers located in the 3’-non-coding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for 190/IV-2, but not for 190/IV-3, a heterozygous insertion of genomic nucleotides -2 and -1, causing a frame-shift after residue 34 of the PrePro sequence and thus 29 novel amino acids without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes AHO-like features, which are similar to those observed with GNAS mutations.

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