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A Heterozygous Splice‐Site Mutation in PTHLH Causes Autosomal Dominant Shortening of Metacarpals and Metatarsals

Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo‐PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha‐subunit of the stimulatory G protein (Gsα). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III‐1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A>G change at nucleotide −3 upstream of PTHLH exon 3 that encodes the last two amino acids of the prosequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II‐2, 190/II‐1), and her affected twin sons (190/IV‐1, 190/IV‐2), but not in her unaffected daughter (190/IV‐3) and sister (190/III‐2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV‐2 (affected) and 190/IV‐3 (unaffected) was PCR‐amplified using forward primers located either in PTHLH exon 1 (noncoding) or exon 2 (presequence and most of the prosequence), and reverse primers located in the 3’‐noncoding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for the affected son 190/IV‐2, but not for the unaffected daughter 190/IV‐3, a heterozygous insertion of genomic nucleotides −2 and −1 causing a frameshift after residue 34 of the pre/prosequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations. © 2018 American Society for Bone and Mineral Research.