Table 5.

Mutations in introns of GHR relevant to human dwarfism due to the failure of GHR expression.

Location	Base Mutation	Defect	Mutation Type	Mechanism	References
Exon 2-intron 2	GT > GGT		Splice site	Results in an immature stop codon in exon 3	[10]
Intron 2	c.70 + 1 G > A 1	70 + 1 G > A		May interfere with GH binding activity	[37]
Intron 4	c.266 + 1 G > A	71 + 1 G > A		Destroys the splice donor and acceptor invariant sequences of consensus sites for mRNA processing	[52,71]
	c.266 + 83 G > T			Results in retention of 81 intronic nucleotides in the GHR mRNA that leads to early protein termination	[65]
Intron 5	c.440 − 1 G > C	IVS5 − 1 G > C		Destroys the splice donor and acceptor invariant sequences of consensus sites for mRNA processing	[71]
Intron 6	c.618 + 18kb A > G	ψ6		Leads to recognition of the pseudoexon and inclusion of an additional 108 bases between exons 6 and 7 that adds 36 amino acids in the GHR ECD	[72]
	c.619 + 1 G > A	IVS6 + 1 G > A		Leads to the skipping of exon 6 and premature termination of the mRNA	[12,44]
	c.619 − 1 G > T	189 − 1 G > T			[71]
	c.619 − 1 G > C	189 − 1 G > C			[50]
	c.619 − 25 A > G	IVS6 − 25 A > G
Intron 7	c. 785 − 1 G > T	785 − 1 G > T		Results in a truncated protein that retains GH binding activity and is probably no longer anchored in the cell membrane, affecting signal transmission
Intron 8	c.876 − 1 C > G	GHR (1–277)		Truncates the ICD of the GHR, which could form a heterodimer with the wild-type GHR, the activity of which is inhibited in a dominant-negative manner	[6,52]
Intron 9	c.945 + 1 G > A	GHR (1–277)		Produces a truncated protein with deletion of 98% of the ICD of the GHR, including Boxes 1 and 2, resulting in failure of GH signal transduction and GHR internalization	[52,67]

¹ c.: coding sequence.