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Context Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis. Objective We hypothesized a heterozygous genetic mutation. Methods This was a family-based study. Two generations of women (proband, sister, and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the 3 women ranged from 0.618 to 1.4 ng/mL (range, 2.8-29.2 ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years. Prolactin gene (PRL) exons 1 to 5 were sequenced. We sought a heterozygous, deleterious gene variant with functional consequences. Results We identified a heterozygous mutation (c.658C &amp;gt; T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A &amp;gt; T; p.Lys218Ter). Conclusion This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.

PRL Mutation Causing Alactogenesis: Insights Into Prolactin Structure and Function Relationships