Relationship Between Hypomorphic Alleles and Mosaicism of Lethal Mutations

(1)

Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany

Abstract

Some genes may harbor different mutant alleles resulting in either a very severe or a rather mild disorder. For example, male embryos hemizygous for incontinentia pigmenti are dying in utero. Remarkably, however, other mutations within the same gene are hypomorphic alleles giving rise to ectodermal dysplasia of Zonana, a disease that is so mild that hemizygous males can survive. Female carriers only show a systematized linear pattern of pigmentary disturbance that should not be confused with incontinentia pigmenti, whereas affected males suffer from a rather severe immunodeficiency. In another X-linked male-lethal trait, Conradi-Hünermann-Happle syndrome, the presence of a hypomorphic allele accounts for survival of men who suffer from “MEND syndrome”, representing a quite different phenotype. A similar dichotomy of severity has been documented in CHILD syndrome versus CK syndrome, and in autosomal dominant acanthosis nigricans versus FGFR3 epidermal nevus syndrome.

Some genes may harbor mutations that are deleterious to such degree that affected embryos can only survive in a mosaic state. For example, male embryos hemizygous for incontinentia pigmenti are dying in utero. Remarkably, however, other mutations within the same gene give rise to ectodermal dysplasia of Zonana, a disorder that is so mild that hemizygous males can survive (Table 4.1). They have the full-blown phenotype including dysgammaglobulinemia and recurrent infections [1, 13]. Female carriers only show a systematized linear pattern of pigmentary disturbance that should not be confused with incontinentia pigmenti which represents a male-lethal trait, whereas ectodermal dysplasia of Zonana is caused by a hypomorphic NEMO mutation [12].

Table 4.1

Genes that may harbor either lethal or hypomorphic alleles

Locus	Gene and its protein	Mosaic phenotype caused by lethal alleles	Nonmosaic phenotype caused by hypomorphic alleles	Is heterozygosity for a hypomorphic allele clinically recognizable?
Xq28	NEMO	Incontinentia pigmenti	Ectodermal dysplasia of Zonana [13]	Yes
Xq28	IKK-gamma	Incontinentia pigmenti	Ectodermal dysplasia of Zonana [13]	Yes
Xp11.22–p11.23	EBP	Conradi-Hünermann-Happle syndrome	MEND syndrome [2, 7]	No
Xp11.22–p11.23	Sterol-Δ⁸-isomerase	Conradi-Hünermann-Happle syndrome	MEND syndrome [2, 7]	No
Xq28	NSDHL	CHILD syndrome [9]	CK syndrome [4, 10]	No
Xq28	3ß-hydroxysteroid dehydrogenase	CHILD syndrome [9]	CK syndrome [4, 10]	No
4p16.3	FGFR3	FGFR3 epidermal nevus syndrome [6]	Autosomal dominant acanthosis nigricans [3]	Yes
4p16.3	Fibroblast growth factor receptor 3	FGFR3 epidermal nevus syndrome [6]	Autosomal dominant acanthosis nigricans [3]	Yes

Similarly, Milunsky et al. [11] described a boy with “a severe atypical phenotype for X-linked dominant Conradi-Hünermann-Happle syndrome.” The child had a multisystem birth defect but no epiphyseal stippling nor any other clinical sign of Conradi-Hünermann-Happle syndrome, although an EBP mutation was found. His mother who carried the same mutation did not show any clinical abnormality. Therefore, one reader argued that this was not a severe form of that X-linked male-lethal disorder but a quite different X-linked recessive phenotype being caused by a hypomorphic EBP allele resulting in survival of the boy [7, 8]. Subsequently similar cases were described [5], and the term MEND syndrome (male EBP disorder with neurological defects) was proposed [2].

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